Prostaglandins and processes for production thereof

ABSTRACT

A prostaglandin having formula (I), (II), or (III): ##STR1## a process of production thereof, and inhibitors of cell migration caused by chemokines containing (I) or (II) as an active ingredient.

TECHNICAL FIELD

The present invention relates to novel prostaglandins having a cellmigration inhibitory activity and useful as pharmaceuticals, processesfor production of the same, intermediates useful in their synthesis, andmedicines containing the same.

BACKGROUND ART

Prostaglandin derivatives have various biological activities such asinhibition of platelet aggregation, a vasodilating activity lowering theblood pressure, suppression of the secretion of gastric acids, smoothmuscle constriction, cytoprotection, and digresis and are useful for thetreatment or prevention of cardiac infarction, angia, arteriosclerosis,hypertension, duodenal ulcers, oxytocia, abortion, etc.

Among these prostaglandin derivatives, as Δ⁸ type prostaglandinderivatives, there have been known the prostaglandin E₁ affines of enolbutyric acid esters of prostaglandin E₁ (see Japanese Unexamined PatentPublication (Kokai) No. 5-213862).

On the other hand, it has been disclosed that 7-thiaprostaglandin E₁derivatives have a platelet aggregation inhibitory activity, hypotensiveactivity, and vasodilating activity and thereby an anti-thrombosis,anti-anginia, anti-cardiac infarction, anti-arteriosclerosis, andmalignant tumor metathesis preventing activity and have an anti-tumoractivity (see Japanese Unexamined Patent Publication (Kokai) No.53-68753, Japanese Unexamined Patent Publication (Kokai) No. 58-110562,Japanese Unexamined Patent Publication (Kokai) No. 59-29661, JapaneseUnexamined Patent Publication (Kokai) No. 60-185761, and JapaneseUnexamined Patent Publication (Kokai) No. 61-204163). Further, these7-thiaprostaglandin E₁ derivatives are known to have effectiveness inthe neuropathy in diabetes (see Japanese Unexamined Patent Publication(Kokai) No. 64-52721). Further, it has been reported that7-thiaprostaglandin E₁ derivatives have an activity suppressingthickening of the veins and an activity inhibiting migration of smoothmuscle cells (see WO95/00150) and an activity inhibiting migration ofTHP-1 cells (see Japanese Unexamined Patent Publication (Kokai) No.7-188025).

Corresponding enol ester derivatives (Δ⁸ type prostaglandin derivatives)are known for the 7-thiaprostaglandin E₁ derivatives as well. These havebeen reported as having an activity suppressing thickening of veins andan activity inhibiting migration of THP-1 cells (see WO/19340).

The enol ester derivatives of these (7-thia)prostaglandin E₁ derivativeshave enol ester portions which easily hydrolyzed in the body due to theaction of esterase and other enzymes and are believed to change to(7-this)prostaglandin E₁ derivatives (9-oxo type). Therefore, these enolester derivatives may be considered prodrugs of (7-thia)prostaglandin E₁derivatives.

The Δ⁸ type prostaglandins of the present invention differ from theseenol ester derivatives in that they are compounds in which substituentsnot easily decomposed by the action of enzymes etc. are introduced atthe 9-position. The inventors studied various compounds which werechemically stable in this way and further exhibited bioactivity in theΔ⁸ state and, as a result, found that these compounds have an inhibitoryactivity on cell migration caused by chemokines and thereby reached thepresent invention.

On the other hand, it has been reported that Δ⁸ type prostaglandinderivatives have a luteal recessive activity and an abortive activity(see DE3125271 or Japanese Unexamined Patent Publication (Kokai) No.58-4763). The Δ⁸ -type prostaglandin derivatives shown here, however,are just derivatives where the 9-position substituent is hydrogen andthe 7-position is methylene. It was not known at all that the compoundsof the present invention have an inhibitory activity on the cellmigration caused by chemokines.

DISCLOSURE OF INVENTION

The problems to be solved by the present invention are to provide novelprostaglandins inhibiting cell migration caused by chemokines, forexample, monocyte chemotactic protein MCP-1MCAF and useful as medicinesfor the treatment of arteriosclerosis, diabetic angiopathy, etc.

Here, "CHEMOKINES" (also known as "INTERCRINES") is the general name forthe polypeptide inflammatory/immunocontrol factors produced from theactive macrophages of the lymph tissue or inflamed portions, white bloodcells, etc., having a molecular weight of approximately 10 Kd, havingfour cysteines, basic, and exhibiting heparin bonding. Their mainactivity is activity causing cell migration. Interleukin-8, MIP-1α/β(abbreviation for Macrophage Inflammatory Protein-1α/β), MCP-1(abbreviation for Monocyte Chemotactic Protein-1), etc. fall under thiscategory. Involvement in various chronic/acute inflammatory diseases issuggested in this cytokine family (see for example, MICHIEL, D. (1993),BIOTECHNOLOGY, vol. 11, p. 739, OPPENHEIM, J. J. et al., (1991), AnnualReview of IMMUNOLOGY, vol. 9, pp. 617-648, NEOTE, K. et al., (1993),CELL, pp. 415-425, SCHALL, T. J. (1991), CYTOKINE, vol. 3, pp. 165-183,etc.) Among these, monocyte chemotatic protein MCP-1 (also known as MCAF(abbreviation for MACROPHAGE CHEMOTACTIC AND ACTIVATING FACTOR) areproduced from T-lympocytes, macrophages, smooth muscle cells,fibroblasts, vascular endothelial cells, etc. along with various stimuliand have migration activity with respect to monocytes, activatedT-cells, and natural killer cells. In diseases in whichmonocyte/macrophage cells and/or activated T-cells and natural killercells are closely involved in the advance of the diseases, for example,resterosis or reocclusion occurring after trauma to the intima ofarteries in angioplasty etc., stenosis or occlusion due mainly toformation of atherosclerosis at the coronary artery or carotid artery,arteriosclerosis occurring in heart transplants, rejection of organtransplants, rheumatoid arthritis, glomerular nephritis, and diabeticmicroangiopathy, the chemokine induces the accumulation of themonocyte/macrophage and/or activated T cells and natural killer cells inthe blood into the lesions, and activates the accumulatedmonocyte/macrophages etc.. Therefore, it is strongly suggested thatMCP-1 is deeply involved in the occurrence and progression of theselesions (see for example, LEONARD, E. J. and YOSHIMURA, T. (1990),IMMUNOLOGY TODAY, vol. 11, pp. 97-101, NELKEN, N. A. et al., THE JOURNALOF CLINICAL INVESTIGATION (1991), vol. 88, pp. 1121-1127, KOCH, A. E. etal., E. JOURNAL OF CLINICAL INVESTIGATION (1992), vol. 90, pp. 772-779,HANAZAWA, S. et al., (1993) THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol.268, pp. 9626-9532, GRAVES, D. T. et al., AMERICAN JOURNAL OF PATHOLOGY(1992), vol. 140, pp. 9-14, EDGINGTON, S. M., BIO/TECHNOLOGY (1993),vol. 11, pp. 676-681, ADAMS, D. H. et al., IMMUNOLOGICAL REVIEWS (1993),vol. 134, pp. 5-19, CARR, M. W. et al., (1994) PROC. NATL. ACAD. SCI.,USA, vol. 91, pp. 3652-3656, ALLAVENA, P. et al., (1994), EUROPEANJOURNAL OF IMMUNOLOGY, vol. 24, pp. 3233-3236, etc.). Drugs whichinhibit the migration of cells caused by MCP-1MCAF are expected to beuseful as drugs for the treatment and/or prevention of restenosis orreocclusion occurring after trauma to the intima of arteries inangioplasty etc., stenosis or occlusion caused primarily by formation ofatherosclerosis in the coronary artery or carotid artery etc.,arteriosclerosis occurring in heart transplants, diabetic angiopathy,glomerular nephritis, rheumatoid arthritis, osteoarthritis, or rejectionof organ transplants, etc.

The present inventors engaged in intensive studies on the possibility ofnovel prostaglandins inhibiting cell migration caused by chemokines and,as a result, found that the prostaglandins of the present invention arepowerful inhibitors of cell migration caused by chemokines, for example,monocyte chemotactic protein MCP-1/MCAF, and thus completed the presentinvention.

That is, in accordance with the present invention, there is provided aprostaglandin which is a compound having the following formula (I):##STR2## an enantiomer thereof, or any mixtures of the enantiomersthereof at any ratio.

In formula (I) italicized small numbers are based on numbering of aprostanoic acid, R¹ indicates a C₁ to C₁₀ straight chain or branchedalkyl group, C₁ to C₈ cycloalkyl group, cyano group, formyl group,carboxyl group, (C₁ to C₅ alkyl)oxycarbonyl group, C₂ to C₇ alkanoylgroup, or a C₁ to C₅ alkyl group substituted with (a) halogen atom(s) orsubstituted or unsubstituted phenyl group(s), Z indicates a hydrogenatom or OR², R² and R³ are the same or different and indicate a hydrogenatom, tri(C₁ to C₇ hydrocarbon)silyl group, or group forming an acetalbond with the oxygen atom of a hydroxy group, R₄ indicates a C₁ to C₈straight chain or branched alkyl group, C₂ to C₈ straight chain orbranched alkenyl group, C₂ to C₈ straight chain or branched alkynylgroup, substituted or unsubstituted phenyl group, substituted orunsubstituted C₃ to C₈ cycloalkyl group, further, a straight chain orbranched (C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or C₂ to C₅alkynyl group) substituted with a (C₁ to C₅ alkoxy group, substituted orunsubstituted phenyl group, substituted or unsubstituted phenoxy group,substituted or unsubstituted C₃ or C₈ cycloalkyl group, or substitutedor unsubstituted heterocyclic group), Y indicates a C₁ to C₅ straightchain or branched alkyl group or CO₂ R⁵, R⁵ indicates a hydrogen atom,C₁ to C₁₀ straight chain or branched alkyl group, C₂ to C₁₀ straightchain or branched alkenyl group, or one equivalent cation, X indicates amethylene group or oxygen atom, W indicates a sulfur atom or a sulfynylgroup or methylene group, and the mark -- indicates a double bond orsingle bond.

In accordance with the present invention, there is further provided aprostaglandin which is a compound having the formula (II): ##STR3## anenantiomer thereof or any mixtures of the enantiomers thereof at anyratio.

In the formula (II), italicized small numbers are based on numbering ofprostanoic acids, V indicates a sulfur atom or sulfinyl group and R³,R⁴, X, Y, Z, and the mark -- have the same definitions as explained inthe above formula (I).

In accordance with the present invention, there is further provided aprostaglandin which is a compound having the formula (III): ##STR4## anenantiomer thereof, or any mixtures of enantiomers thereof at any ratio.

In the formula (III), italicized small numbers are based on numbering ofprostanoic acids, W¹ indicates a sulfur atom or methylene group, and R³,R⁴, X, Y, Z, and the mark -- have the same definitions as explained inthe above formula (I).

BEST MODE FOR CARRYING OUT THE INVENTION

In the prostaglandins of the above formula (I), R¹ indicates a C₁ to C₁₀straight chain or branched alkyl group, C₃ to C₈ cycloalkyl group,formyl group, carboxyl group, (C₁ to C₅ alkyl)oxycarbonyl group, C₂ toC₇ alkanoyl group (number of carbon atoms includes carbonyl carbon, samebelow) or a C₁ to C₅ alkyl group substituted with (a) halogen atom(s) orsubstituted or unsubstituted phenyl group(s).

As preferable examples of the C₁ to C₁₀ straight chain or branched alkylgroup, a methyl group, ethyl group, propyl group, isopropyl group, butylgroup, isobutyl group, sec-butyl group, tert-butyl group, pentyl group,isopentyl group, neopentyl group, hexyl group, 3,3-dimethylbutyl group,heptyl group, octyl group, nonyl group, decyl group, etc. may bementioned.

As preferable examples of the C₃ to C₈ cycloalkyl group, a cyclopropylgroup, cyclopentyl group, cyclohexyl group, cyclohexenyl group,cycloheptyl group, cycloctyl group, etc. may be mentioned.

As preferable examples of the (C₁ to C₅ alkyl)oxycarbonyl group, amethoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group,sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonylgroup, isopentyloxycarbonyl group, etc. may be mentioned.

As preferable examples of the C₂ to C₇ alkanoyl group, an acetyl group,propionyl group, butyryl group, isobutyryl group, valeryl group,isovaleryl group, pivaroyl group, etc. may be mentioned.

As preferable examples of the alkyl group of the substituted C₁ to C₅alkyl group with the halogen atom(s) or substituted or unsubstitutedphenyl group(s), the C₁ to C₅ alkyl groups among the preferable examplesof the above-mentioned C₁ to C₁₀ straight chain or branched alkyl groupmay be mentioned as preferable examples.

As the halogen atom serving as a substituent bonding with the C₁ to C₅alkyl group, a fluorine atom or chlorine atom may be mentioned. One ormore of these halogen atoms may be substituted at any position of the C₁to C₅ alkyl group. One or more of the substituted or unsubstitutedphenyl groups serving as the substituent bonding with the C₁ to C₅ alkylgroup may be substituted at any position of the C₁ to C₅ alkyl group. Asthe substituent of the phenyl group, (a) C₁ to C₅ alkyl group(s) orhalogen atom(s) may be mentioned as preferable examples. As the C₁ to C₅alkyl group serving as the substituent bonding with the phenyl group,the above preferable examples of the C₁ to C₁₀ alkyl group where thereare 1 to 5 carbon atoms may be mentioned. One or more of these alkylgroups may be bonded at any position of the phenyl group. As the halogenatom serving as the substituent bonding with the phenyl group, afluorine atom or chlorine atom may be mentioned as preferable examples.One or more of these halogen atoms may be substituted at any position ofthe phenyl group. In the case of plural substituents, any combination ofthe illustrated substituents may be used. Among these, a methyl group isparticularly preferred as R¹.

In the prostaglandins of the above formula (I), Z indicates a hydrogenatom or OR².

In the prostaglandins having the above formula (I), R² and R³ may be thesame or different and indicate a hydrogen atom, tri(C₁ to C₇hydrocarbon)silyl group, or group forming an acetal bond with the oxygenatom of a hydroxy group. As preferable examples of the tri(C₁ to C₇hydrocarbon)silyl group, a trimethylsilyl group, tert-butyldimethylsilylgroup, or other tri(C₁ to C₄ alkyl)silyl group, tert-butyldiphenylsilylgroup or other diphenyl(C₁ to C₄)alkylsilyl group, tribenzylsilyl group,etc. may be mentioned. Further, as preferable examples of the groupforming an acetal bond with the oxygen atom of a hydroxy group, amethoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group,2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, benzyloxymethylgroup, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group,6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hexan-4-yl group, etc. may bementioned. Among these, as R² and R³, a hydrogen atom ortert-butyldimethylsilyl group is particularly preferred and as Z ahydrogen atom or hydroxy group is preferred.

In the prostaglandins having the above formula (I), R⁴ indicates a C₁ toC₈ straight chain or branched alkyl group, C₂ to C₈ straight chain orbranched alkenyl group, C₂ to C₈ straight chain or branched alkynylgroup, substituted or unsubstituted phenyl group, substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a (C₁ to C₅ alkoxy group,substituted or unsubstituted phenyl group, substituted or unsubstitutedphenoxy group, substituted or unsubstituted C₃ to C₁₀ cycloalkyl group,or substituted or unsubstituted heterocyclic group) substituted straightchain or branched (C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or C₂to C₅ alkynyl group).

As preferable examples of the C₁ to C₈ straight chain or branched alkylgroup, a methyl group, ethyl group, propyl group, butyl group, pentylgroup, hexyl group, heptyl group, octyl group, 1-methyl-1-butyl group,2-methylhexyl group, 2-hexyl group, and 1,1-dimethylpentyl group may bementioned.

As preferable examples of the C₂ to C₈ straight chain or branchedalkenyl group, an allyl group, 3-butenyl group, 2-butenyl group,4-pentenyl group, and 2-pentenyl group may be mentioned.

As preferable examples of the C₂ to C₈ straight chain or branchedalkynyl group, an ethynyl group, 2-propynyl group, 1-propynyl group,2-butynyl group, 3-butynyl group, 3-hexynyl group, and1-methyl-3-hexynyl group may be mentioned.

Further, as preferable examples of the substituent in the case where R⁴is a substituted phenyl group, a hydroxyl group, C₂ to C₇ alkanoyloxygroup, C₁ to C₄ alkyl group, C₁ to C₄ alkoxy group, cyano group, nitrogroup, carboxyl group, (C₁ to C₆ alkyl)oxycarbonyl group, etc. may bementioned. One or more of these substituents may be substituted at anyposition of the phenyl group. In the case of plural substituents, anycombination of the illustrated substituents may be used.

As preferable examples of the C₁ to C₅ alkoxy group serving as asubstituent in the (C₁ to C₅ alkoxy group, substituted or unsubstitutedphenyl group, substituted or unsubstituted phenoxy group, substituted orunsubstituted C₃ to C₈ cycloalkyl group, or substituted or unsubstitutedheterocyclic group) substituted straight chain or branched (C₁ to C₅alkyl group, C₂ to C₅ alkenyl group, or C₂ to C₅ alkynyl group), amethoxy group, ethoxy group, propoxy group, isopropoxy group, butoxygroup, tert-butoxy group, hexyloxy group, etc. may be mentioned. Aspreferable examples of the C₃ to C₈ cycloalkyl group serving as thesubstituent, the preferred examples of the cycloalkyl groups of theabove-mentioned R¹ may be mentioned. As preferable examples of theheterocyclic group serving as the substituent, a thienyl group, furanylgroup, imidazolyl group, pyridyl group, pyrazynyl group, etc. may bementioned. Among these substituents, a phenyl group, phenoxy group,cycloalkyl group, or heterocyclic group may further be substituted. Aspreferable examples of the substituent in this case, halogen atom,hydroxyl group, C₂ to C₇ acyloxy group, halogen atom-substitutable C₁ toC₄ alkyl group, halogen atom-substitutable C₁ to C₄ alkoxy group, cyanogroup, nitro group, carboxyl group, (C₁ to C₆)alkoxycarbonyl group, etc.may be mentioned. These substituents may be substituted at any of theortho, meta, and para positions on the phenyl group. Further, anycombination of a plurality of substituents may be used for thesubstitution.

As the straight chain or branched C₁ to C₅ alkyl group, C₂ to C₅ alkenylgroup, and C₂ to C₅ alkynyl, a methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, allyl group, 3-butenyl group, 2-butenylgroup, 4-pentenyl group, 2-pentenyl group, ethynyl group, 2-propynylgroup, 1-propynyl group, 2-butynyl group, 3-butynyl group, etc. may bementioned. The above substituent may be bonded at any position of the C₁to C₅ alkyl group, C₂ to C₅ alkenyl group, or C₂ to C₅ alkynyl group.

Among these, as R⁴, a C₃ to C₈ straight chain or branched alkyl group,substituted or unsubstituted C₃ to C₁₀ cycloalkyl group, or substitutedor unsubstituted phenyl group-substituted straight chain or branched C₁to C₅ alkyl group is preferred, in particular, a pentyl group,2-methylhexyl group, cyclohexyl group, and substituted or unsubstitutedbenzyl group are particularly preferred.

In the prostaglandins of the above formula (I), Y indicates a C₁ to C₅straight chain or branched alkyl group or CO₂ R⁵. R⁵ indicates ahydrogen atom, C₁ to C₁₀ straight chain or branched alkyl group, or C₂to C₁₀ straight chain or branched alkenyl group or one equivalent ofcations.

Here, as the C₁ to C₅ straight chain or branched alkyl group serving asY, a methyl group, ethyl group, propyl group, isopropyl group, butylgroup, isobutyl group, sec-butyl group, tert-butyl group, pentyl group,etc. may be mentioned.

When R⁵ indicates a C₁ to C₁₀ straight chain or branched alkyl group orC₂ to C₁₀ straight chain or branched alkenyl group, as preferableexamples of the C₁ to C₁₀ straight chain or branched alkyl group, amethyl group, ethyl group, propyl group, isopropyl group, butyl group,isobutyl group, sec-butyl group, tert-butyl group, pentyl group,isopentyl group, neopentyl group, hexyl group, heptyl group, octylgroup, nonyl group, decyl group, etc. may be mentioned. Further, aspreferable examples of the C₂ to C₁₀ straight chain or branched alkenylgroup, a vinyl group, allyl group, 3-butenyl group, 2-butenyl group,4-pentenyl group, 2-pentenyl group, prenyl group (3-methyl-2-butenylgroup), 2,4-hexadienyl group, 2,6-octadienyl group, etc. may bementioned.

As preferable examples of the one equivalent cation, NH₄ ⁻,tetramethylammonium, monomethylammonium, dimethylammonium,trimethylammonium, benzylammonium, phenetylammonium, morpholiniumcations, monoethanolammonium, piperidinium cations, and other ammoniumcations; Na⁺, K⁺, and other alkali metal cations; 1/2 Ca²⁺, 1/2 Mg²⁺,1/2 Zn²⁺, 1/3 Al³⁺, and other bivalent or trivalent metal cations etc.may be mentioned. Among these, as R⁵, a hydrogen atom or methyl group isparticularly preferred.

In the prostaglandins having the above formula (I), X indicates amethylene group or oxygen atom. Among these, as X, a methylene group ispreferred.

In the prostaglandins having the above formula (I), W indicates a sulfuratom or sulfinyl group or methylene group. Among these, as W, a sulfuratom is most preferred.

In the prostaglandins having the above formula (I), the mark --indicates a double bond or single bond. Among these, one where the mark-- indicates a double bond is most preferred.

Further, the compounds having the above formula (I) wherein theconfiguration of the substituent bonded on the cyclopentenone ring isthe configuration derived from natural prostaglandin are particularlyuseful stereoisomers, but the present invention also includes theirenantiomers, that is, stereoisomers having the following formula(I)ent.: ##STR5##

wherein, R¹, R³, R⁴, W, X, Y, Z, and the mark -- have the samedefinitions as explained above or any mixture thereof at any ratio.Further, since an OR³ or R⁴ substituted carbon is an asymmetric carbonatom, there are two types of optical isomers. Either of these opticalisomers or any mixture thereof at any ratio are also included.

As preferable specific examples of the prostaglandins having the aboveformula (I) of the present invention, the compounds shown below may bementioned.

01) (11R,12R,13E,15S)-11,15-dihydroxy-9-methylprosta-8,13-dienoic acid

02) (11R,12R,13E,15S)-11,15-dihydroxy-9-ethylprosta-8,13-dienoic acid

03) (11R,12R,13E,15S)-11,15-dihydroxy-9-propylprosta-8,13-dienoic acid

04) (11R,12R,13E,15S)-11,15-dihydroxy-9-isopropylprosta-8,13-dienoicacid

05) (11R,12R,13E,15S)-11,15-dihydroxy-9-butylprosta-8,13-dienoic acid

06) (11R,12R,13E,15S)-11,15-dihydroxy-9-isobutylprosta-8,13-dienoic acid

07) (11R,12R,13E,15S)-11,15-dihydroxy-9-sec-butylprosta-8,13-dienoicacid

08) (11R,12R,13E,15S)-11,15-dihydroxy-9-tert-butylprosta-8,13-dienoicacid

09) (11R,12R,13E,15S)-11,15-dihydroxy-9-pentylprosta-8,13-dienoic acid

10) (11R,12R,13E,15S)-11,15-dihydroxy-9-cyclopropylprosta-8,13-dienoicacid

11) (11R,12R,13E,15S)-11,15-dihydroxy-9-neopentylprosta-8,13-dienoicacid

12) (11R,12R,13E,15S)-11,15-dihydroxy-9-hexylprosta-8,13-dienoic acid

13)(11R,12R,13E,15S)-11,15-dihydroxy-9-(3,3-dimethylbutyl)prosta-8,13-dienoicacid

14) (11R,12R,13E,15S)-11,15-dihydroxy-9-heptylprosta-8,13-dienoic acid

15) (11R,12R,13E,15S)-11,15-dihydroxy-9-octylprosta-8,13-dienoic acid

16) (11R,12R,13E,15S)-11,15-dihydroxy-9-cyclohexylprosta-8,13-dienoicacid

17) (11R,12R,13E,15S)-11,15-dihydroxy-9-decylprosta-8,13-dienoic acid

18) (11R,12R,13E,15S)-11,15-dihydroxy-9-cyanoprosta-8,13-dienoic acid

19) (11R,12R,13E,15S)-11,15-dihydroxy-9-formylprosta-8,13-dienoic acid

20) (11R,12R,13E,15S)-11,15-dihydroxy-9-carboxyprosta-8,13-dienoic acid

21)(11R,12R,13E,15S)-11,15-dihydroxy-9-methoxycarbonylprosta-8,13-dienoicacid

22)(11R,12R,13E,15S)-11,15-dihydroxy-9-ethoxycarbonylprosta-8,13-dienoicacid

23)(11R,12R,13E,15S)-11,15-dihydroxy-9-propoxycarbonylprosta-8,13-dienoicacid

24)(11R,12R,13E,15S)-11,15-dihydroxy-9-isopropoxycarbonylprosta-8,13-dienoicacid

25)(11R,12R,13E,15S)-11,15-dihydroxy-9-butoxycarbonylprosta-8,13-dienoicacid

26)(11R,12R,13E,15S)-11,15-dihydroxy-9-tert-butoxycarbonylprosta-8,13-dienoicacid

27)(11R,12R,13E,15S)-11,15-dihydroxy-9-pentyloxycarbonylprosta-8,13-dienoicacid

28) (11R,12R,13E,15S)-11,15-dihydroxy-9-acetylprosta-8,13-dienoic acid

29) (11R,12R,13E,15S)-11,15-dihydroxy-9-propionylprosta-8,13-dienoicacid

30) (11R,12R,13E,15S)-11,15-dihydroxy-9-butyrylprosta-8,13-dienoic acid

31) (11R,12R,13E,15S)-11,15-dihydroxy-9-isobutyrylprosta-8,13-dienoicacid

32) (11R,12R,13E,15S)-11,15-dihydroxy-9-valerylprosta-8,13-dienoic acid

33) (11R,12R,13E,15S)-11,15-dihydroxy-9-isovalerylprosta-8,13-dienoicacid

34) (11R,12R,13E,15S)-11,15-dihydroxy-9-pivaroylprosta-8,13-dienoic acid

35)(11R,12R,13E,15S)-11,15-dihydroxy-9-trifluoromethylprosta-8,13-dienoicacid

36)(11R,12R,13E,15S)-11,15-dihydroxy-9-trichloromethylprosta-8,13-dienoicacid

37) (11R,12R,13E,15S)-11,15-dihydroxy-9-fluoromethylprosta-8,13-dienoicacid

38) (11R,12R,13E,15S)-11,15-dihydroxy-9-chloromethylprosta-8,13-dienoicacid

39) (11R,12R,13E,15S)-11,15-dihydroxy-9-phenethylprosta-8,13-dienoicacid

40)(11R,12R,13E,15S)-11,15-dihydroxy-9-(3-phenylpropyl)prosta-8,13-dienoicacid

41)(11R,12R,13E,15S)-11,15-dihydroxy-9-(4-phenylbutyl)prosta-8,13-dienoicacid

42) (11R,12S,13E,15S)-11,15-dihydroxy-9-methyl-7-thiaprosta-8,13-dienoicacid

43) (11R,12S,13E,15S)-11,15-dihydroxy-9-ethyl-7-thiaprosta-8,13-dienoicacid

44)(11R,12S,13E,15S)-11,15-dihydroxy-9-cyclopropyl-7-thiaprosta-8,13-dienoicacid

45)(11R,12S,13E,15S)-11,15-dihydroxy-9-(3,3-dimethylbutyl)-7-thiaprosta-8,13-dienoicacid

46) (11R,12S,13E,15S)-11,15-dihydroxy-9-cyano-7-thiaprosta-8,13-dienoicacid

47) (11R,12S,13E,15S)-11,15-dihydroxy-9-formyl-7-thiaprosta-8,13-dienoicacid

48)(11R,12S,13E,15S)-11,15-dihydroxy-9-carboxy-7-thiaprosta-8,13-dienoicacid

49)(11R,12S,13E,15S)-11,15-dihydroxy-9-methoxycarbonyl-7-thiaprosta-8,13-dienoicacid

50) (11R,12S,13E,15S)-11,15-dihydroxy-9-acetyl-7-thiaprosta-8,13-dienoicacid

51)(11R,12S,13E,15S)-11,15-dihydroxy-9-trifluoromethyl-7-thiaprosta-8,13-dienoicacid

52)(11R,12S,13E,15S)-11,15-dihydroxy-9-phenethyl-7-thiaprosta-8,13-dienoicacid

53)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9,17,20-trimethylprosta-8,13-dienoicacid

54)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-pentyl-17,20-dimethylprosta-8,13-dienoicacid

55)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-cyano-17,20-dimethylprosta-8,13-dienoicacid

56)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-formyl-17,20-dimethylprosta-8,13-dienoicacid

57)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-methoxycarbonyl-17,20-dimethylprosta-8,13-dienoicacid

58)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-acetyl-17,20-dimethylprosta-8,13-dienoicacid

59)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-trifluoromethyl-17,20-dimethylprosta-8,13-dienoicacid

60)(11R,12R,13E,15S,17R)-11,15-dihydroxy-9-cyclopropyl-17,20-dimethylprosta-8,13-dienoicacid

61)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9,17,20-trimethyl-7-thiaprosta-8,13-dienoicacid

62)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-pentyl-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

63)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-(3,3-dimethylbutyl)-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

64)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-cyano-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

65)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-formyl-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

66)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-methoxycarbonyl-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

67)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-acetyl-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

68)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-trifluoromethyl-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

69)(11R,12S,13E,15S,17R)-11,15-dihydroxy-9-phenethyl-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

70)(11R,12R,13E,15S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

71)(11R,12R,13E,15S)-11,15-dihydroxy-9-pentyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

72)(11R,12R,13E,15S)-11,15-dihydroxy-9-cyano-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

73)(11R,12R,13E,15S)-11,15-dihydroxy-9-formyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

74)(11R,12R,13E,15S)-11,15-dihydroxy-9-methoxycarbonyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

75)(11R,12R,13E,15S)-11,15-dihydroxy-9-acetyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

76)(11R,12R,13E,15S)-11,15-dihydroxy-9-trifluoromethyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

77)(11R,12R,13E,15S)-11,15-dihydroxy-9-phenethyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

78)(11R,12S,13E,15S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

79)(11R,12S,13E,15S)-11,15-dihydroxy-9-pentyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

80)(11R,12S,13E,15S)-11,15-dihydroxy-9-cyano-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

81)(11R,12S,13E,15S)-11,15-dihydroxy-9-formyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

82)(11R,12S,13E,15S)-11,15-dihydroxy-9-methoxycarbonyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

83)(11R,12S,13E,15S)-11,15-dihydroxy-9-acetyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

84)(11R,12S,13E,15S)-11,15-dihydroxy-9-trifluoromethyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

85)(11R,12S,13E,15S)-11,15-dihydroxy-9-phenethyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

86)(11R,12S,13E,15S)-11,15-dihydroxy-9-cyclopropyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

87)(12R,13E,15S)-15-hydroxyl-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

88)(11R,12S,15R)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoicacid

89)(11R,12S,13E,15S)-11,15-dihydroxy-9-trifluoromethyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

90)(11R,12S,13E,15S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

91)(11R,12R,13E,15S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

92)(11R,12S,13E,15S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-sulfinylprosta-8,13-dienoicacid

93)(11R,12S,13E,15R,16S)-11,15-dihydroxy-9,16-dimethyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

94)(11R,12S,13E,15R,16R)-11,15-dihydroxy-9,16-dimethyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

95)(12R,13E,15R)-15-hydroxy-9,16-dimethyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

96)(12R,13E,15S)-15-hydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

97)(12R,13E,15S)-15-hydroxy-9-methyl-16-cyclohexyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

98)(12R,15R)-15-hydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8-eneacid

99)(12R,15R)-15-hydroxy-9-methyl-15-cyclohexyl-16,17,18,19,20-pentanol-3-oxa-7-thiaprosta-8-enoicacid

100)(12R,13E,15S)-15-hydroxy-9-methyl-18-phenyl-19,20-dinol-3-oxa-7-thiaprosta-8,13-dienoicacid

101)(12R,13E,15S,17R)-15-hydroxy-9,17,20-trimethyl-3-oxa-7-thiaprosta-8,13-dienoicacid

102)(12R,13E,15S)-15-hydroxy-9-methyl-16-(2-thienyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

103)(12R,13E,15R)-15-hydroxy-9-methyl-16-phenoxy-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

104)(12R,13E,15S)-15-hydroxy-9-methyl-3-oxa-7-thiaprosta-8,13-dien-17-inoicacid

105)(12R,13E,15S,17E)-15-hydroxy-9,17-dimethyl-3-oxa-7-thiaprosta-8,13,17-trienoicacid

106)(12R,13E,15R)-15-hydroxy-9-methyl-15-phenyl-16,17,18,19,20-pentanol-3-oxa-7-thiaprosta-8,13-dienoicacid

107)(12R,13E,15R)-15-hydroxy-9-methyl-16-ethoxy-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

108)(12R,13E,15S)-15-hydroxy-9-methyl-16-(3-chlorophenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

109)(12R,13E,15R,16E)-15-hydroxy-9-methyl-17-(3-hydroxylphenyl)-18,19,20-trinol-3-oxa-7-thiaprosta-8,13,16-trienoicacid

110)(12R,13E,15S)-15-hydroxy-9-methyl-16-(3-methylphenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

111)(12R,13E,15R)-15-hydroxy-9-methyl-15-(3-cyanophenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

112)(12R,13E,15R)-15-hydroxy-9-methyl-15-(3-methoxyphenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

113)(12R,13E,15R)-15-hydroxy-9-methyl-15-(4-hydroxylphenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

114)(12R,13E,15R)-15-hydroxy-9-methyl-15-(3-acetoxyphenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

115)(12R,13E,15R)-15-hydroxy-9-methyl-15-(3-nitrophenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

116)(12R,13E,15R)-15-hydroxy-9-methyl-15-(3-carboxyphenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

117)(12R,13E,15R)-15-hydroxy-9-methyl-15-(2-methoxycarbonylphenyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

118)(12R,13E,15R)-15-hydroxy-9-methyl-15-(4-imidazolyl)-16,17,18,19,20-pentanol-3-oxaprosta-8,13-dienoicacid

119)(12R,13E,15S)-15-hydroxy-9-methyl-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranol-3-oxaprosta-8,13-dienoicacid

120)(12R,13E,15S)-15-hydroxy-9-methyl-16-(3-acetoxyphenyl)-17,18,19,20-tetranol-3-oxaprosta-8,13-dienoicacid

121)(12R,13E,15S)-15-hydroxy-9-methyl-16-[4-(2-chloroethoxy)phenyl]-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

122)(12R,13E,15S)-15-hydroxy-9-methyl-16-(4-cyanophenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

123)(12R,13E,15S)-15-hydroxy-9-methyl-16-(3-carboxyphenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

124)(12R,13E,15S)-15-hydroxy-9-methyl-16-(4-nitrophenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

125)(12R,13E,15S)-15-hydroxy-9-methyl-16-(4-methoxycarbonylphenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

126)(12R,13E,15S)-15-hydroxy-9-methyl-16-(3-pyridyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

127)(12R,13E,15S)-15-hydroxy-9-methyl-16-(2-furanyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

128) Enantiomers of the compounds of 01) to 127)

129) Methyl esters of the compounds of 01) to 127)

130) Ethyl esters of the compounds of 01) to 127)

131) Butyl esters of the compounds of 01) to 127)

132) Allyl esters of the compounds of 01) to 127)

133) Sodium salts of the compounds of 01) to 127)

134) Compounds of the compounds of 01) to 127) where the carboxyl group(portion shown by Y) is substituted by a methyl group

135) Ethers of the compounds of 01) to 127) where the hydroxy groups(11-position and 15-position) are protected by a tert-butyldimethylsilylgroup and/or trimethylsilyl group and/or 2-tetrahydropyranyl group etc.may be mentioned, but the invention is not limited to these. Further,optical isomers of the hydroxy group (15-position) portion of the ωchain of the compounds of 01) to 135) and all of their enantiomers maybe mentioned.

On the other hand, in the prostaglandins of the above formula (II), Vindicates a sulfur atom or sulfinyl group. As a preferable example, asulfur atom may be mentioned. As specific examples of R³, R⁴, X, Y, Z,and the mark --, those mentioned as specific examples of R³, R⁴, X, Y,Z, and the mark -- in the above formula (I) may be mentioned as theyare. Further, as preferable examples of these, those the same as in thecase of the above formula (I) may be mentioned.

Further, the compounds of the above formula (II) wherein theconfiguration of the substituent bonded on the cyclopentenone ring isthe configuration derived from natural prostaglandin are particularlyuseful stereoisomers, but the present invention also includes theirenantiomers, that is, stereoisomers having the following formula(II)ent.: ##STR6##

wherein, R³, R⁴, V, X, Y, Z, and the mark -- have the same definitionsas explained above, or any mixture thereof at any ratio. Further, sincean OR³ or R⁴ substituted carbon is an asymmetric carbon, there are twotypes of optical isomers. Either of these optical isomers or anymixtures thereof at any ratio are also included.

As preferable specific examples of the prostaglandins having the aboveformula (II) of the present invention, the compounds shown below may bementioned:

201) (11R,12S,13E,15S)-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid

202)(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

203)(11R,12S,13E,15S)-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

204)(11R,12S,13E,15S)-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-sulfinylprosta-8,13-dienoicacid

205)(12R,13E,15R)-15-hydroxy-16-(4-chlorophenyl)-16-methyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

206)(12R,15R)-15-hydroxy-16-(4-nitrophenyl)-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8-eneacid

207) Enantiomers of the compounds of 201) to 206)

208) Methyl esters of the compounds of 201) to 206)

209) Ethyl esters of the compounds of 201) to 206)

210) Butyl esters of the compounds of 201) to 206)

211) Allyl esters of the compounds of 201) to 206)

212) Sodium salts of the compounds of 201) to 206)

213) Compounds of the compounds of 201) to 206) where the carboxyl group(portion shown by Y) is substituted by a methyl group

214) Ethers of the compounds of 201) to 206) where the hydroxy groups(11-position and 15-position) are protected by a tert-butyldimethylsilylgroup and/or trimethylsilyl group and/or 2-tetrahydropyranyl group etc.may be mentioned, the present invention is not limited thereto. Further,optical isomers of the hydroxy group (15-position) portion of the ωchain of the compounds of 201) to 214) and all of their enantiomers maybe mentioned.

Further, in the prostaglandins having the above formula (III), W¹indicates a sulfur atom or methylene group, as a preferable example ofwhich a sulfur atom may be mentioned. As specific examples of R³, R⁴, X,Y, Z, and the mark --, those mentioned as specific examples of R³, R⁴,X, Y, Z, and the mark -- in the above formula (I) may be mentioned.Further, as preferable examples thereof, the same ones as in the case ofthe above formula (I) may be mentioned.

Further, the compounds having the above formula (III) wherein theconfiguration of the substituent bonded on the cyclopentenone ring isthe configuration derived from natural prostaglandin are particularlyuseful stereoisomers, but the present invention also includes theirenantiomers, that is, stereoisomers having the following formula(III)ent.: ##STR7##

wherein, W¹, R³, R⁴, X, Y, Z, and the mark -- have the same definitionsas explained above, or any mixture thereof at any ratio. Further, sincean OR³ or R⁴ substituted carbon is an asymmetric carbon, there are twotypes of optical isomers. Either of these optical isomers or any mixturethereof at any ratio are also included.

As preferable specific examples of the prostaglandins having the aboveformula (III) according to the present invention, the compounds shownbelow may be mentioned.

301)(11R,12R,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-dihydroxyprosta-8,13-dienoicacid

302)(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoicacid

303)(11R,12R,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoicacid

304)(11R,12S,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoicacid

305)(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid

306)(11R,12S,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

307)(11R,12S,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

308)(12R,13E,15S)-9-trifluoromethanesulfonyloxy-15-hydroxy-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoicacid

309)(12R,13E,15S)-9-trifluoromethanesulfonyloxy-15-hydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid

310)(12R,13E,15S)-9-trifluoromethanesulfonyloxy-15-hydroxy-16-phenyl-17,18,19,20-tetranol-prosta-8,13-dienoicacid

311) Enantiomers of the compounds 301) to 310)

312) Methyl esters of the compounds 301) to 310)

313) Ethyl esters of the compounds 301) to 310)

314) Butyl esters of the compounds 301) to 310)

315) Allyl esters of the compounds 301) to 310)

316) Sodium salts of the compounds 301) to 310)

317) Compounds of the compounds 301) to 310) where the carboxyl group(portion shown by Y) is substituted by a methyl group

318) Ethers of the compounds 301) to 310) where the hydroxy groups(11-position and 15-position) are protected by a tert-butyldimethylsilylgroup and/or trimethylsilyl group and/or 2-tetrahydropyranyl group etc.may be mentioned, but the present invention is not limited to these.Further, optical isomers of the hydroxy group (15-position) portion ofthe ω chain of the compounds of 301) to 318) and all of theirenantiomers may be mentioned.

Further, the process of production of the prostaglandins according tothe present invention having the above formulas (I), (II), and (III) isincluded in the present invention. That is, it comprises effecting areaction between an organocopper compound prepared from

an organolithium compound having the formula (IV): ##STR8##

wherein, R⁴ has the same definition as explained above, and R³¹indicates a tri(C₁ to C₇ hydrocarbon)silyl group or group forming anacetal bond with the oxygen atom of a hydroxy group and

an organocopper compound prepared from a copper reagent having theformula:

    CuQ

wherein, Q indicates a 1-hexynyl group, 1-pentynyl group, or cyanogroup, and

a 2-cyclopentenone having the formula (V): ##STR9##

wherein, Z¹ indicates a hydrogen atom or OR²¹, R²¹ indicates a tri(C₁ toC₇ hydrocarbon)silyl group or group forming an acetal bond with theoxygen atom of a hydroxy group, Y¹ indicates a C₁ to C₅ straight chainor branched alkyl group or CO₂ R⁵¹, R⁵¹ indicates a C₁ to C₁₀ straightchain or branched alkyl group or C₂ to C₁₀ straight chain or branchedalkenyl group, and W¹ and X have the same definitions as explainedabove] or its enantiomer or a mixture thereof at any ratio, then,further, causing a reaction with an sulfonimide acid having the formula(VI): ##STR10##

wherein, A indicates a hydrogen atom or chlorine atom and D indicates anitrogen atom or methine group to obtain the synthetic intermediatehaving the formula (VII): ##STR11##

wherein, R³¹, R⁴, W¹, X, Y¹, Z¹, and the mark -- have the samedefinitions as explained above, or its enantiomer or any mixture thereofat any ratio.

The synthetic process of the synthetic intermediate compound (VII)including the synthesis of the compound (III) may be illustrated as inscheme 1. ##STR12##

in which scheme, R³, R³¹, R⁴, W¹, X, Y¹ Y, Z¹, Z, A, D, and the mark --have the same definitions as explained above.

In Scheme 1, if the starting material is made a racemate, since thesynthesis proceeds stereospecifically with the intermediate as a mixtureof the compound of the scheme and its enantiomers, if one of thecompounds of the above formula (IV) or the above formula (V) isoptically active, it is possible to separate it at a suitable stage (anystage of Scheme 1 or any stage in the synthesis of the compound (I) orcompound (II) from the compound (III) so as to isolate the individualstereoisomers as pure products.

In the conjugate addition reaction of the first step of the methodaccording to the present invention (Scheme 1), if, together with theorganocopper compound, a trivalent organophosphorus compound, forexample, trialkylphosphine (e.g., triethylphosphine, tributylphosphine,etc.), trialkylphosphate (e.g., trimethyl-phosphate, triethylphosphate,triisobutylphosphate, tributylphosphate, etc.), hexamethylphosphorustriamide, or triphenylphosphine is used, the conjugate addition reactionwill proceed more smoothly. In particular, tributylphosphine orhexamethylphosphorus triamide is preferably used.

The process according to the present invention comprises effecting areaction in the presence of an aprotonic inert organic solvent betweenan organolithium compound having the above formula (IV) and anorganocopper compound prepared from CuQ, wherein Q has the samedefinition as explained above and a 2-cyclopentenone having the aboveformula (V), then effecting a reaction with the sulfonimide having theabove formula (VI).

A 2-cyclopentenone and organocopper compound react equimolarlystoichiochemically, but usually 0.5 to 5.0, preferably 0.8 to 2.0,particularly preferably 1.0 to 1.5 moles of an organocopper compound areused based upon 1 mole of a 2-cyclopentenone.

The conjugate addition reaction of the 2-cyclopentenone and organocoppercompound is carried out at a temperature range of -100° C. to 50° C.,particularly preferably -78° C. to 0° C. The reaction time differsdepending upon the reaction temperature, but usually it is sufficient toeffect the reaction for about 1 hour at -78° C. to -20° C.

The reaction intermediate obtained by a conjugate addition reaction of a2-cyclopentenone and organocopper compound reacts stoichiochemicallyequimolarly with sulfonimide, but usually the reaction is carried outunder conditions giving an excess of sulfonimide. That is, the reactionis performed using 1.0 to 10.0, preferably 1.0 to 5.0 moles ofsulfonimide based upon 1 mole of 2-cyclopentenone.

The reaction between the reaction intermediate obtained by a conjugateaddition reaction of a 2-cyclopentenone and organocopper compound andthe sulfonimide is carried out at a temperature of -30° C. to 50° C.,particularly preferably -30° C. to 30° C. or so. The reaction timediffers depending upon the reaction temperature, but usually it issufficient to carry out the reaction for about 15 minutes at 0° C. to20° C.

This reaction is carried out in the presence of an inert aprotonicorganic solvent which is liquid under the reaction temperature and doesnot react with the reaction reagents. As the aprotonic inert organicsolvent, for example, saturated hydrocarbons such as pentane, hexane,heptane, cyclohexane, aromatic hydrocarbons such as benzene, toluene,xylene, ether type solvents such as diethylether, tetrahydrofuran,dioxane, dimethoxyethane, diethylene glycol dimethylether, and alsoother so-called aprotonic polar solvents such ashexamethylphospholicamide (HMP), N,N-dimethylformamide (DMF),N,N-dimethylacetoamide (DMA), dimethylsulfoxide (DMSO), sulforan,N-methylpyridone may be mentioned. Any mixture of the two or more typesof these solvents may be used. Further, as the aprotonic inert organicsolvent, the inert solvent used to prepare the organocopper compound maybe used as it is. That is, in this case, the reaction may be carried outby adding into a reaction system used for preparing the organocoppercompound a 2-cyclopentenone. The amount of the organic solvent used needonly be an amount sufficient for the smooth progress of the reaction.Normally, 1 to 100 times the volume of the starting material, preferably2 to 20 times, is used.

As explained above, it is possible to make a trivalent organophosphoruscompound be present at the time of preparation of the organocoppercompound and possible to add to that system a 2-cyclopentenone toperform the reaction. As a result, a compound (VII) of the compoundhaving the above formula (III) where the hydroxy group is protected andthe R⁵ portion is an ester is obtained.

The process of production according to the present invention uses areaction which proceeds stereospecifically, so compounds having theconfiguration of the above formula (III) are obtained from startingmaterials having the configuration of the above formula (V) andcompounds having the configuration of the following formula (VII)ent.:##STR13##

wherein R³¹, R⁴, W¹, X, Y¹, Z¹, and the mark -- are the same as in theabove formula are obtained from the enantiomers having the above formula(V).

After the reaction, the resultant product is separated from the reactionsolution and purified by an ordinary means such as extraction, washing,chromatography, or any combinations thereof.

The compound (VII) obtained by the above method wherein the hydroxygroup is protected and the COOR⁵ portion serving as Y is an ester may,optionally, have the protection removed or be subjected to hydrolysis.The protecting group (R²¹ and/or R³¹) of the hydroxy group may beremoved by, when the protecting group is a group forming an acetal bondtogether with the oxygen atom of the hydroxy group, by using, forexample, acetic acid, a p-toluenesulfonic acid pyridinium salt, orcation ion exchange resin as a catalyst and using for example, water,tetrahydrofuran, dioxane, acetone, acetonitrile, etc. as a reactionsolution. The reaction is normally performed at a temperature range of-78° C. to 50° C. for 10 minutes to 3 days or so. Further, when theprotecting group is a tri(C₁ to C₇ hydrocarbon)silyl group, for example,the protecting group may be removed under similar conditions usingacetic acid, p-toluenesulfonic acid pyridinium salt, tetrabutylammoniumfluoride, cesium fluoride, hydrofluoric acid, orhydrogenfluoride-pyridine as a catalyst.

In the case of a compound where the protecting group is removed and thewater solubility is high, the ester of the compound where the COOR⁵portion is an ester may be hydrolyzed by effecting a reaction using orexample lipase, esterase, or other enzyme in water or a solventcontaining water at a temperature range of -10° C. to 60° C. for 10minutes to 24 hours.

Further, as shown below, it is possible to derive from a compound havingthe above formula (VII) a compound of the above formula (I) or (II) byvarious reactions using a palladium catalyst.

The prostaglandin of the present invention having the above formula (I)where R¹ is a C₁ to C₁₀ straight chain or branched alkyl group, cyanogroup, or halogen- or substituted or unsubstituted phenylgroup-substituted C₁ to C₅ alkyl group may be produced by effectingcoupling in an inert gas atmosphere in the presence of a palladiumcatalyst between a compound having the above formula (VII) or itsenantiomer or any mixture of the enantiomers at any ratio and

an organoboron compound having the following formula (VIII): ##STR14##

wherein, R¹¹ indicates a C₁ to C₁₀ straight chain or branched alkylgroup or C₁ to C₅ alkyl group substituted with (a) halogen atom(s) orsubstituted or unsubstituted phenyl group(s).

an organoaluminum compound having R¹² ₃ Al

wherein, R¹² indicates a C₁ to C₁₀ straight chain or branched alkylgroup or a substituted or unsubstituted phenyl group-substituted C₁ toC₅ alkyl group,

an organozinc compound having R¹³ ZnI

wherein, R¹³ indicates a C₁ to C₁₀ straight chain or branched alkylgroup or a fluorine atom-substituted C₁ to C₅ alkyl group,

an organotin compound of R¹⁴ SnBu₃

wherein, R¹⁴ indicates a C₁ to C₁₀ straight chain or branched alkylgroup or a substituted or unsubstituted phenyl group-substituted C₁ toC₅ alkyl group, or

a cyanide having LCN

wherein, L indicates a sodium atom or a potassium atom

to obtain a compound having the following formula (I-1): ##STR15##

wherein, R¹⁵ indicates a C₁ to C₁₀ straight chain or branched alkylgroup, cyano group, or halogen atom- or substituted or unsubstitutedphenyl group-substituted C₁ to C₅ alkyl group and R³¹, R⁴, W¹, X, Y¹,Z¹, and the mark -- have the same definitions as explained above, itsenantiomer or any mixture thereof at any ratio and, optionally, byremoving the protection and/or performing a hydrolysis reaction.

The synthesis process of the prostaglandins according to the presentinvention having the above formula (I) where R¹ indicates a C₁ to C₁₀straight chain or branched alkyl group, cyano group, or halogen- orsubstituted or unsubstituted phenyl group-substituted C₁ to C₅ alkylgroup, if illustrated from the compound (VII), becomes as shown inScheme 2: ##STR16##

in which scheme, R¹⁵ M indicates a compound having the above formula(VIII), R¹² ₃ Al, R¹³ ZnI, R¹⁴ SnBu₃, or LCN. R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R³, R³¹, R⁴, W¹, X, Y, Y¹, Z, Z¹, and the mark -- have the samedefinitions as explained above.

In the coupling reaction of the first step of the method according tothe present invention (Scheme 2), as the palladium catalyst, a 0-valentor bivalent complex may be used. For example,tris(benzylidenacetone)dipalladium (0),bis[1,2-bis(diphenylphosphino)ethane]palladium (0),tetrakistriphenylphosphinepalladium (0), palladium acetate,bistriphenylphosphinepalladium(II)acetate,bistriphenylphosphinepalladium(II)chloride, etc. may be mentioned. Toreduce the amount of the palladium complex required to end the reaction,it is sometimes better to add to the reaction system phosphine oranother ligand. In particular, with a palladium complex where there isno phosphine ligand in the complex such astris(dibenzylidenacetone)dipalladium(0) or palladium acetate, in manycases the reaction is performed adding a ligand to the reaction system.As the ligand added, triphenylphosphine, diphenylphosphinoethane,tributylphosphine, triethylphosphine, triethylphosphate, etc. may bementioned. The amount of the palladium complex usable for the reactionis 0.1 to 50 mol % based upon the substrate compound (VII). The amountof addition in the case of adding a ligand is 0.2 to 8 equivalents or sobased upon the palladium.

The coupling reaction of the first step is performed in the presence ofan organic solvent. An inert aprotonic organic solvent which is liquidunder the reaction temperature and does not react with the reactionreagents is used. As this aprotonic inert organic solvent, for example,aromatic hydrocarbons such as pentane, hexane, heptane, cyclohexane, orother saturated hydrocarbon, benzene, toluene, xylene, ether solventssuch as diethylether, tetrahydrofuran, dioxane, dimethoxyethane,diethylene glycol dimethylether, or other so-called aprotonic polarsolvents such as hexamethylphospholicamide (HMP), N,N-dimethylformamide(DMF), N,N-dimethylacetoamide (DMA), dimethylsulfoxide (DMSO), sulforan,N-methylpyrrolidone may be mentioned. Two or more types of solvents maybe also used as a mixture together. The amount of the organic solventused need only be such that the reaction is smoothly proceeded.Normally, 1 to 100 times, preferably 2 to 20 times, of the organicsolvent, based upon the volume of the starting material is used.

The coupling reaction of the first step is performed using anorganoboron compound, organoaluminum compound, organozinc compound,organotin compound, or cyan compound. These need only bestoichiochemically equimolar with the substrate compound (VII), but inactuality 0.5 to 10.0 equivalents are used. Preferably 1.0 to 5.0equivalents are used. The coupling reaction of the first step is carriedout at a reaction temperature of about 0 to 100° C., preferably, 15 to70° C.

Note that when using an organoboron compound to carry out the couplingreaction, it is necessary to place a base such as tripotassiumphosphate, sodium hydroxide, sodium ethoxide, lithium hydroxide, sodiumhydrogencarbonate in the system. This base need only bestoichiochemically equimolar with the substrate compound (VII), butpractically 0.5 to 10.0 equivalents are used. Preferably 1.0 to 5.0equivalents are used. As a result, the compound having the above formula(I-1) is obtained.

After the reaction, the resultant product is separated from the reactionsolution and refined by a means such as the removal of catalyst byFlorisil or Celite filtration, extraction, washing, chromatography, etc.

The compound thus obtained (compound where the hydroxy group isprotected and the COOR⁵ portion serving as Y is an ester) may have theprotection removed and be hydrolyzed by a method similar to the methodmentioned in the explanation of Scheme 1.

The prostaglandins according to the present invention having the aboveformula (I) where R¹ indicates a formyl group are produced bycarbonylating a compound having the above formula (VII) or itsenantiomer or any mixture thereof at any ratio, for example, in a 1 to50 atmosphere carbon monoxide atmosphere using a palladium catalyst, byreacting the intermediate with hydrogen gas or ammonium formate orformic acid and a tertiary amine salt to obtain a compound having theformula (I-2): ##STR17##

wherein, R¹⁶ is a formyl group and R³¹, R⁴, W¹, X, Y¹, Z¹, and the mark-- have the same definitions as explained above or its enantiomer or anymixture thereof at any ratio and, optionally removing the protectionand/or applying a hydrolysis reaction.

The synthesis process of the prostaglandin according to the presentinvention having the above formula (I) where R¹ is a formyl group, ifillustrated from compound (VII), becomes as shown in Scheme 3. ##STR18##

in which scheme, R¹⁶, R³, R³¹, R⁴, W¹, X, Y, Y¹, Z, Z¹, and the mark --have the same definitions.

As specific examples of the palladium catalyst used in the formylationreaction of the first step of the method according to the presentinvention (Scheme 3) and the amount used, the catalysts and amounts usedmentioned in the explanation of the reaction of the first step of Scheme2 may be applied as they are.

The formylation reaction of the first step is carried out in thepresence of an organic solvent. As the specific solvent and the amountused, the solvents and amounts used mentioned in the explanation of thereaction of the first step of Scheme 2 may be applied as they are.

The formylation reaction of the first step of Scheme 3 requires that thecompound (VII) be carbonylated in a carbon monoxide atmosphere, buttherefore the reaction vessel must be subjected to a pressure of about 1to 50 atmospheres by carbon monoxide. To carry out the reaction quickly,a higher carbon monoxide pressure is advantageous.

Further, in this formylation, the reaction intermediate produced fromthe compound (VII) and carbon monoxide must be reacted with hydrogen,but, as the hydrogen source, it is possible to use hydrogen gas orammonium formate or formic acid and a tertiary amine salt. When usinghydrogen gas, it is sufficient to include it as a gaseous mixture withthe carbon monoxide. The ratio of the hydrogen gas and carbon monoxideis 1 to 9 to 9 to 1. When using ammonium formate or formic acid and atertiary amine salt as the hydrogen source, it must bestoichiochemically equimolar with respect to the substrate compound(VII), but 0.5 to 10.0 equivalents as formic acid is practically used.Preferably 1.0 to 5.0 equivalents are used. Commercially availableammonium salts may be used as they are or triethylamine or another basemay be added to formic acid dissolved in a solution to adjust theacidity. The amount of the base used is basically equimolar with theformic acid and the reaction system is made neutral, but considering theacid resistance and base resistance of the reaction substrate, theconditions need not be neutral so long as the conditions are such thatthe compound will not decompose.

The reaction temperature of the formylation reaction of the first stepof Scheme 3 is about 0 to 150° C. It is difficult to perform thereaction at a temperature above the boiling point of the solvent used inusual reactions, but when using a pressure resistant vessel, it ispossible to perform the reaction at a temperature over the boiling pointof the solvent. As a result, a compound having the above formula (I-2)is obtained.

After the reaction, the resultant product is separated from the reactionsolution and refined by a means such as, the removal of the catalyst byFlorisil or Celite filtration or extraction, washing, chromotography,etc.

The compound thus obtained (compound where the hydroxy group isprotected and the COOR⁵ portion as Y is an ester) may have theprotection removed and be hydrolyzed by a method similar to the methodmentioned in the explanation of Scheme 1.

The compounds of the prostaglandins according to the present inventionhaving the above formula (I) where R¹ indicates a carboxyl group or (C₁to C₅ alkyl)oxycarbonyl group are produced by placing a compound of theabove formula (VII) or its enantiomer or any mixture thereof at anyratio in a carbon monoxide atmosphere in the presence of a C₁ to C₅alcohol or water and performing carbonylation using a palladium catalystto obtain a compound having the following formula (I-3): ##STR19##

wherein, R¹⁷ indicates a carboxyl group or C₁ to C₅ alkoxycarbonylgroup, and R³¹, R⁴, W¹, X, Y¹, Z¹, and the mark--have the samedefinitions as explained above, or its enantiomer or any mixture thereofat any ratio and, optionally, removing the protection and/or performinga hydrolysis reaction.

The synthesis path of the prostaglandins of the present invention havingthe above formula (I), wherein R¹ is a carboxyl group or (C₁ to C₅alkyl)oxycarbonyl group, if illustrated from the compound (VII), becomesas shown in Scheme 4. ##STR20##

in which scheme, R¹⁷, R³, R³¹, R⁴, W¹, X, Y, Y¹, Z, Z¹, and themark--have the same definitions as explained above.

In the carbonylation reaction of the first step of the method accordingto the present invention (Scheme 4), as the palladium catalyst, a0-valent or bivalent complex may be used. For example,tris(benzylideneacetone)dipalladium (0),bis[1,2-bis(diphenylphosphin)ethane]palladium(0),tetrakistriphenylphosphinepalladium(0), palladium acetate,bistriphenylphosphinepalladium(II)acetate, etc. may be mentioned. Forthe amount of use of the palladium catalyst and the use of ligands, theexamples in the explanation of the reaction of the first step of Scheme2 apply as they are

The carbonylation reaction of the first step of Scheme 4 is carried outin the presence of an organic solvent. As the specific solvent and theamount used, the solvents and amounts used mentioned in the explanationof the reaction of the first step of Scheme 2 may be used.

The carbonylation reaction of the first step of Scheme 4 requires thatthe compound (VII) be carbonylated in a carbon monoxide atmosphere.Therefore, the reaction vessel must be pressurized by carbon monoxide tonormally 1 to 50 atmospheres or so. To carry out the reaction quickly, ahigher carbon monoxide pressure is advantageous.

Further, in this carbonylation reaction, the reaction intermediateproduced from the compound (VII) and carbon monoxide is reacted with thewater or alcohol present in the system. The water or alcohol need bestoichiochemically equimolar, but practically 0.5 to 10.0 equivalentsare used. Preferably 1.0 to 5.0 equivalents are used.

The carbonylation reaction of the first step is carried out at areaction temperature of about 0 to 100° C., preferably, 15 to 70° C. Asa result, the compound of the above formula (I-3) is obtained.

After the reaction, the resultant product is separated from the reactionsolution and refined by a means such as the removal of the catalyst byFlorisil or Celite filtration extraction, washing, chromotography, etc.

The compound thus obtained (compound where the hydroxy group isprotected and the COOR⁵ portion serving as Y is an ester) may have theprotection removed and be hydrolyzed by a method similar to the methodmentioned in the explanation of Scheme 1.

The prostaglandins according to the present invention having the aboveformula (I), wherein R¹ is a C₂ to C₇ alkanoyl group, are produced byreacting the compound having the above formula (VII) or its enantiomeror any mixture thereof at any ratio in a carbon monoxide atmosphere witha palladium catalyst and

an organoboron compound having the formula (VIII'): ##STR21##

wherein, R¹¹¹ indicates a C₁ to C₆ straight chain or branched alkylgroup;

an organoaluminum compound having the formula:

    R.sup.121.sub.3 Al

wherein, R¹²¹ indicates a C₁ to C₆ straight chain or branched alkylgroup;

an organozine compound having the formula:

    R.sup.131 ZnI

wherein, R¹³¹ indicates a C₁ to C₆ straight chain or branched alkylgroup;

or an organotin compound having the formula:

    R.sup.141 SnBu.sub.3

wherein, R¹⁴¹ indicates a C₁ to C₆ straight chain or branched alkylgroup to obtain the alkanoylated compound having the following formula(I-4): ##STR22##

wherein, R¹⁸ indicates a C₂ to C₇ alkanoyl group and R³¹, R⁴, W¹, X, Y¹,Z¹ and the mark--have the same definitions as explained above or itsenantiomer or any mixture of the enantiomers at any ratio and,optionally, removing the protection and/or applying a hydrolysisreaction.

The synthesis process of the prostaglandins according to the presentinvention having the above formula (I) where R¹ is an C₁ to C₇ alkanoylgroup, if illustrated from compound (VII), becomes as shown in theScheme 5. ##STR23##

in which Scheme, R¹⁰⁰ M indicates one of a compound having the aboveformula (VIII'), R¹²¹ ₃ Al, R¹³¹ ZnI, or R¹⁴¹ SnBu₃ and R¹¹¹, R¹²¹,R¹³¹, R¹⁴¹, R³, R³¹, R⁴, W¹, X, Y, Y¹, Z, Z¹, and the mark--have thesame definitions.

In the alkanoylation reaction of the first step of the method accordingto the present invention (Scheme 5), as the palladium catalyst, a0-valent complex may be used. For example, tris(benzylideneacetone)dipalladium(0),bis[1,2-bis(diphenylphosphin)ethane]palladium(0),tetrakistriphenylphosphinepalladium(0), etc. may be mentioned. Theamount of the palladium catalyst used and the ligands mentioned in theexplanation of the reaction according to the first step of Scheme 2 maybe used.

The alkanoylation reaction according to the first step of Scheme 5 isperformed in the presence of an organic solvent. As the specific solventand the amount used, the solvents and amounts used mentioned in theexplanation of the reaction of the first step of Scheme 2 may be used.

The alkanoylation reaction of the first step of Scheme 5 requires thatthe compound (VII) be carbonylated in a carbon monoxide atmosphere.Therefore, the reaction vessel must be pressurized by carbon monoxide tonormally 1 to 50 atmospheres or so. To carry out the reaction quickly, ahigher carbon monoxide pressure is advantageous.

Further, in this reaction, the reaction intermediate produced from thecompound (VII) and carbon monoxide reacts with an organoboron compound,organoaluminum compound, organozinc compound, or organotin compound.These have to be stoichiochemically equimolar to the substrate compound(VII), but in actuality 0.5 to 10.0 equivalents are used. Preferably 1.0to 5.0 equivalents are used. The alkanoylation reaction of the firststep is performed at a reaction temperature of about 0 to 150° C. As aresult, the compound of the above formula (I-4) is obtained.

After the reaction, the resultant product is separated from the reactionsolution and refined by a means such as the removal of the catalyst byFlorisil or Celite filtration extraction, washing, chromotography, etc.

The compound thus obtained (compound where the hydroxy group isprotected and the COOR⁵ portion serving as Y is an ester) may have theprotection removed and be hydrolyzed by a method similar to the methodmentioned in the explanation of Scheme 1.

The process of production of the prostaglandins according to the presentinvention having the above formula (II), comprises reducing a compoundhaving the following formula (VII'): ##STR24##

wherein, R³¹, R⁴, X, Y¹, Z¹, and the mark--have the same definitions asexplained above or its enantiomer or any mixture of the enantiomers atany ratio in the presence of a palladium catalyst by formic acid and,optionally need, removing the protection and/or applying a hydrolysisreaction.

The synthesis process of the prostaglandins according to the presentinvention having the above formula (II), if illustrated from compound(VII'), becomes as shown in the Scheme 6. ##STR25##

in which scheme, R³, R³¹, R⁴, X, Y, Y¹, Z, Z¹, and the mark--have thesame definitions as explained above.

As the palladium catalyst used in the reduction reaction of the firststep of the method according to the present invention (Scheme 6) and theamount used, the catalysts and amounts used mentioned in the explanationof the reaction according to the first step of Scheme 2 may be used.Further, regarding the amount of the ligand used, the examples given inthe explanation of the reaction according to the first step of Scheme 2may be applied as they are.

The reduction reaction of the first step is carried out in the presenceof an organic solvent. As the specific solvent and the amount used, thesolvents and amounts used mentioned in the explanation of the reactionof the first step of Scheme 2 may be used.

The reduction reaction of the first step is carried out on the compound(VII') using formic acids as a hydrogen source, but as the formic acids,in addition to formic acid, ammonium formate or formic acid and atertiary amine salt may be used. The ammonium formate or formic acid andtertiary amine salt have to be stoichiochemically equimolar with thesubstrate compound (VII'), but practically 0.5 to 10.0 equivalents asformic acid are used. Preferably 1.0 to 5.0 equivalents are used.Commercially available ammonium salts may be used as they are ortriethylamine or another base may be added to formic acid dissolved in asolution to adjust the acidity. The amount of the base used is basicallyequimolar with the formic acid and the reaction system is made neutral,but considering the acid resistance and base resistance of the reactionsubstrate, the conditions need not be neutral so long as the conditionsare such that the compound will not decompose. The reduction reaction ofthe first step is carried out at a reaction temperature of about 0 to100° C. Preferably it is performed at about 20 to 70° C.

As a result, a compound having the above formula (II) where the hydroxygroup is protected and the COOR⁵ portion serving as Y is an ester isobtained. After the reaction, the product thus obtained is separatedfrom the reaction solution and refined by a means the removal of thecatalyst by Florisil or Celite filtration or such as extraction,washing, chromotography, etc.

The compound thus obtained (compound where the hydroxy group isprotected and the COOR⁵ portion serving as Y is an ester) may have theprotection removed and be hydrolyzed by a method similar to the methodmentioned in the explanation of Scheme 1.

The prostaglandins of the present invention having the above formula (I)where R¹ indicates a C₃ to C₈ cycloalkyl group or straight chain orbranched C₁ to C₁₀ alkyl group are synthesized from compound (VII) bythe synthesis process of the following (Scheme 7). ##STR26##

in which scheme, R¹⁹ indicates a C₃ to C₈ cycloalkyl group or straightchain or branched C₁ to c₁₀ alkyl group and R³, R³¹, R⁴, W¹, X, Y, Y¹,Z, Z¹, and the mark--have the same definitions as explained above.

The reaction of the first step according to the process of the presentinvention (Scheme 7) is performed in the presence of an aprotonic inertorganic solvent by reacting an organocopper compound and a compoundhaving the above formula (VII).

The compound having the above formula (VII) and organocopper compoundreact stoichiochemically equimolarly, but usually 0.5 to 5.0, preferably0.8 to 2.0, particularly preferably 1.0 to 1.5 moles of organocoppercompound based upon 1 mole of the compound of formula (VII) is used. Thereaction is carried out at a temperature of -100° C., to 50° C.,particularly preferably -78° C. to 10 C.

The reaction is carried out in the presence of an organic solvent. Aninert aprotonic organic solvent, which is liquid at the reactiontemperature, is used and does not react with the reaction reagents. Asexamples of this aprotonic inert organic solvent, the solvents mentionedin the explanation of Scheme 1, which may be used in similar amounts,are used.

After the reaction, the product thus obtained is separated and refinedby ordinary means. For example, this is performed by extraction,washing, chromatography, or the combinations thereof.

The compound thus obtained (compound where the hydroxy group isprotected and the COOR⁵ portion as Y is an ester) may have theprotection removed and be hydrolyzed by a method similar to the methodmentioned in the explanation of Scheme 1.

The prostaglandins of the present invention having the above formula (I)or (II) where W or V is a sulfinyl group may be easily synthesized byconverting the sulfur atom of the above compounds (I-1), (I-2), (I-3),(I-4), (I-5) or the compound having the following formula (X): ##STR27##

wherein R³¹, R⁴, X, Y¹, Z¹, and the mark--have the same definitions asexplained above to a sulfinyl group by oxidation by peracid or peroxideand, optionally, having the protection removed and/or applying ahydrolysis reaction.

According to the present invention, a compound having a carboxyl groupobtained from the above hydrolysis reaction may, optionally, further besubjected to a salt producing reaction to obtain the correspondingcarboxylate. The salt producing reaction is performed by neutralizationby an equal amount as the carboxylic acid of potassium hydroxide, sodiumhydroxide, sodium carbonate, or other basic compound, or ammonia,trimethylamine, monoethanolamine, morpholine, etc. by an ordinarymethod.

Further, according to the present invention, there is provided apharmaceutical composition comprised of an amount of a prostaglandins ofthe present invention or their salt effective for treatment and apharmacologically allowable carrier. Note that the prostaglandins of thepresent invention may also be used formed as an inclusion compound of α,β, or γ-cyclodextrin etc.

When clinically applying the prostaglandins of the present invention ortheir salts or compounds containing the same for example as a medicinefor the prevention or treatment of reconstriction after PTCA, theprostaglandins are used as active ingredients with a solid, liquid, orother pharmaceutically allowable carrier to form a pharmaceuticalcomposition. Further, in accordance with need, it is preferable to add adiluent, that is, an excipient, stabilizer, or other additive to makethe preparation. An injection use preparation of the prostaglandins ofthe present invention to be administered for therapeutical use mustnormally be in a sterile state. Sterility may be easily achieved byfiltration through a pore size 0.2 μm membrane filter or othersterilizing filter membrane.

The ratio of the above-mentioned active ingredient in the carriercomponent in the pharmaceutical composition concerned may be changedbetween 1.0 to 90% w/w. The effective dosage for treatment depends onthe method of administration, the age, the disease concerned, etc., butin general is 1 μg to 10 mg/day/person. For the individual means ofadministration, it is desirable to determine the efficiency ofabsorption into the body for each compound by pharmacologically knownmethods.

As the form of the medicines and means of administration, the medicinesmay be formed into granules, powders, dispersions, pills, tablets,capsules, liquids, or other forms and be administered orally or may beformed into suppositories, aerosols, or ointments and dermal patches andother local preparations etc. and administered nonorally. The injectionmay be administered intravenously, intraarterially, intramuscularly, orsubcutaneously. Further, it may be made into an injection powder andprepared at the time of use.

A pharmaceutical use organic or inorganic solid or liquid carrier ordiluent suited for oral, rectal, or nonoral administration may be usedto prepare the prostaglandins of the present invention as pharmaceuticalpreparations. As the typical carriers or diluents capable of formulatingin the tablets, capsules, etc., binders such as acacia, corn starch, orgelatin, excipients such as microcrystalline cellulose, decay agentssuch as corn starch, alginic acid, lubricants such as magnesiumstearate, sweeteners such as sucrose, lactose, may be mentioned. In thecase of capsules, in addition to the above substances, it is possible toadd liquid carriers such as fatty acids. It is possible to use varioustypes of other substances as coatings or as agents for improving thephysical shape of the dosage units. The injection use sterilecomposition may be prepared in accordance with conventionalpharmacological methods. For example, the active compounds arepreferably dissolved or suspended in water or natural vegetable oils orother excipients or ethyl oleate and other synthetic fatty excipients.It is also possible to incorporate citrates, acetates, phosphates, andother buffers, ascorbic acid and other antioxidants in accordance withallowable pharamacological methods.

EXAMPLES

The present invention will be further verified below according to theExamples, but the present invention is of course not limited in scope bythese Examples.

Example 1

Synthesis of methyl(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoate##STR28##

(1E,3S,5R)-1-iodo-3-(tert-butyldimethylsiloxy)-5-methyl-1-nonene (951mg, 2.4 mmol) in ether (6 mL) was cooled to -78° C., thentert-butyllithium (1.54 mol/L, 3.12 mL, 4.8 mmol) was added. This wasagitated at -78° C. for 2 hours. Further, to this were added1-hexynylcopper (I) (347 mg, 2.4 mmol) and hexamethylphosphorus triamide(872 μl, 4.8 mmol) in ether (6 mL). This was agitated at -78° C. for afurther 1 hour to give copper reagent. To the obtained copper reagentwas drop-wise added(4R)-tert-butyldimethylsiloxy-2-(6-methoxycarbonylhexyl)-2-cyclopenten-1-one(709 mg, 2.0 mmol) in tetrahydrofuran (40 mL). The reaction mixture wasagitated at -78° C. for 15 minutes, then the reaction temperature wasraised and it was agitated at -50 to -30° C. for 1 hour to object aconjugate adduct. To the resultant conjugate adduct was added at -30° C.N-phenyltrifluoromethane-sulfonimide (1.07 mg, 3.0 mmol) intetrahydrofuran (6 mL). This was agitated for 15 hours while raising thereaction temperature to room temperature. The reaction solution waspoured into saturated ammonium sulfate (100 mL) to end the reaction. Themixture was separated, then the aqueous layer was extracted with etherand the extract was combined with the organic layer, then dried overanhydrous magnesium sulfate. The solution was concentrated under reducedpressure, then was purified by silica gel column chromotography (2 to 5%ethyl acetate/hexane) to obtain methyl(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoate (627 mg,41%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.00, 0.01, 0.05 (s, 12H), 0.8-0.9 (m,6H), 0.87 (s, 9H), 0.89 (s, 9H), 1.0-1.7 (m, 17H), 2.1-2.3 (m, 2H), 2.30(t, J=7.6 Hz, 2H), 2.46 (d, J=15.8 Hz, 1H), 2.91 (dd, J=6.9 & 16.2 Hz,1H), 3.04 (d, J=8.9 Hz, 1H), 3.67 (s, 3H), 4.0-4.2 (m, 2H), 5.32 (dd,J=9.2 & 15.5 Hz, 1H), 5.56 (dd, J=5.9 & 15.5 Hz, 1H),

Example 2

Synthesis of methyl(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate##STR29##

As a byproduct of the reaction of Example 6, methyl(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate(48 mg) is obtained. See Example 6.

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H), 1.1-2.0 (m, 17H),2.1-2.4 (m, 2H), 2.30 (t, J=7.4 Hz, 2H), 2.56 (dd, J=4.5 & 16.0 Hz, 1H),2.95 (dd, J=7.3 & 15.8 Hz, 1H), 3.10 (dd, J=3.6 & 8.9 Hz, 1H), 3.67 (s,3H), 4.1-4.3 (m, 2H), 5.45 (dd, J=8.9 & 15.2 Hz, 1H), 5.63 (dd, J=6.6 &15.2 Hz, 1H)

Example 3

Synthesis of methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR30##

(1E,3S,5R)-1-iodo-3-(tert-butyldimethylsiloxy)-5-methyl-1-nonene (476mg, 1.2 mmol) in ether (3 mL) was cooled to -78° C., thentert-butyllithium (1.54 mol/L, 1.56 mL, 2.4 mmol) was added. This wasagitated at -78° C. for 2 hours. Further, to this were added1-hexynylcopper (I) (174 mg, 1.2 mmol) and hexamethylphosphorus triamide(436 μl, 2.4 mmol) in ether (6 mL). This was agitated at -78° C. for afurther 1 hour to give copper reagent. To the copper reagent thusobtained was drop-wise added(4R)-tert-butyldimethylsiloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopenten-1-one(373 mg, 1.0 mmol) in tetrahydrofuran (20 mL). The reaction mixture wasagitated at -78° C. for 15 minutes, then the reaction temperature wasraised and it was agitated at -50 to -30° C. for 1 hour to obtain aconjugate adduct. To the obtained conjugate adduct was added at -30° C.N-phenyltrifluoromethanesulfonimide (429 mg, 1.2 mmol) intetrahydrofuran (5 mL). This was agitated for 15 hours while raising thereaction temperature to room temperature. The reaction solution waspoured into saturated ammonium sulfate (65 mL) to end the reaction. Themixture was separated, then the aqueous layer was extracted with ether.The extract was combined with the organic layer, then dried overanhydrous magnesium sulfate. The solution was concentrated under reducedpressure, then was purified by silica gel column chromotography (2 to 5%ethyl acetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(410 mg, 52%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.03, 0.05, 0.06 (s, 12H), 0.8-0.9 (m,6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.0-1.7 (m, 15H), 2.31 (t, J=7.4 Hz,2H), 2.4-2.9 (m, 3H), 2.97 (dd, J=6.3 & 16.2 Hz, 1H), 3.16 (d, J=7.9 Hz,1H), 3.67 (s, 3H), 4.0-4.2 (m, 2H), 5.41 (dd, J=8.4 & 15.3 Hz, 1H), 5.64(dd, J=5.4 & 15.7 Hz, 1H)

Example 4

Synthesis of methyl(11R,12S,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR31##

(1E,3S)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butene (699 mg)in ether (4 mL) was cooled to -78° C., then tert-butyllithium (1.50mol/L, 2.40 mL) was added. This was agitated at -78° C. for 1 hour.Further, to this were added 1-hexynylcopper (I) (260 mg) andhexamethylphosphorus triamide (654 μl) in ether (10 mL). This wasagitated at -78° C. for a further 1 hour to give copper reagent. To theresultant copper reagent was drop-wise added(4R)-tert-butyldimethylsiloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopenten-1-one(560 mg) in tetrahydrofuran (20 mL). The reaction mixture was agitatedat -78° C. for 1 hour, then the reaction temperature was raised and itwas agitated at -50 to -40° C. for 30 minutes to obtain a conjugateadduct. To the obtained conjugate adduct was added at -40° C.N-phenyltrifluoromethanesulfonimide (1.47 mg) in tetrahydrofuran (13mL). The solution was agitated for 1 hour, while raising the reactiontemperature to room temperature. The reaction solution was poured intosaturated ammonium sulfate (100 mL) to end the reaction. The mixture wasseparated, then the aqueous layer was extracted with ether and theextract was combined with the organic layer, then dried over anhydrousmagnesium sulfate. The solution was concentrated under reduced pressure,then was purified by silica gel column chromotography (3 to 4% ethylacetate/hexane) to obtain methyl(11R,12S,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(983 mg, 86%).

¹ H-NMR (270M Hz, δppm, CDCl₃): -0.25 (s, 3H), -0.09 (s, 3H), 0.04 (s,3H), 0.06 (s, 3H), 0.85 (s, 9H), 0.87 (s, 9H), 1.3-1.7 (m, 6H), 2.31 (t,J=7.3 Hz, 3H), 2.4-2.6 (m, 2H), 2.65-2.8 (m, 3H), 2.93 (ddd, J=1.6 & 6.2& 14.9 Hz, 1H), 3.14 (d, J=8.9 Hz, 1H), 3.66 (s, 3H), 4.0-4.03 (m, 1H),5.28 (dd, J=4.9 & 11.6 Hz, 1H), 5.43 (ddd, J=1.0 & 8.2 & 15.5 Hz, 1H),5.67 (dd, J=5.3 & 15.5 Hz, 1H), 7.1-7.3 (m, 5H)

Example 5

Synthesis of methyl(11R,12R,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoate##STR32##

To tetrakistriphenylphosphinepalladium prepared in advance in the systemfrom tris(dibenzylideneacetone) dipalladium(0) (46 mg, 0.05 mmol) andtriphenylphosphine (105 mg, 0.4 mmol) were addedmethyl(11R,12R,13E,15S,17R)-9-trifluoromethane-sulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoate(379 mg, 0.5 mmol) in a 1,2-dichloroethane (5 mL) solution and 2Mtrimethylaluminum in hexane (0.375 mL, 0.75 mmol). This was agitated for3 hours at room temperature. Ether was added to dilute the reactionsolution, then the solution was poured in 1N hydrochloric acid. Thedesired product was extracted with ether from the mixture. The extractwas washed with brine, then was dried over anhydrous sodium sulfate. Thesolution was concentrated under reduced pressure, then was purified bysilica gel column chromotography (2% ethyl acetate/hexane) to obtainmethyl(11R,12R,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoicacid as a mixture with the unreactedmethyl(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoicacid etc. (174 mg). The NMR data for the mixture was measured, but couldnot be analyzed. This mixture was subjected to the operation of Example6 without further purification.

Example 6

Synthesis of methyl(11R,12R,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate##STR33##

To a solution of ice-cooled acetonitrile (2 ml) and pyridine (0.2 mL)was added hydrogen fluoride-pyridine (0.2 mL). To this solution wasadded a mixture (174 mg) containing methyl(11R,12R,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoatein pyridine (0.2 mL). The ice bath was removed and the solution wasagitated for 15 hours while returning it to room temperature. Thereaction solution was poured into a mixture of ethyl acetate and asaturated aqueous solution of sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromotography (30 to 50% ethyl acetate/hexane) andsubjected to thin layer chromotography for separation (ethylacetate:hexane=4:1) to obtain methyl(11R,12R,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate(21 mg, 2 step 10%) and as a byproduct, methyl(11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate(48 mg, 2 step, 18%).

¹ H NMR (270M Hz, δppm, CDCl₃): 0.8-1.0 (m, 6H), 1.1-1.9 (m, 17H), 1.64(d, J=0.7 Hz, 3H), 2.0-2.4 (m, 3H), 2.30 (t, J=7.4 Hz, 2H), 2.62 (dd,J=6.6 & 16.2 Hz, 1H), 3.04 (d, J=7.3 Hz, 1H), 3.66 (s, 3H), 4.0-4.2 (m,1H), 4.1-4.3 (m, 1H), 5.40 (dd, J=8.9 & 15.5 Hz, 1H), 5.54 (dd, J=6.8 &15.3 Hz, 1H)

¹³ C-NMR (67.5 MHz, δppm, CDCl₃): 14.0, 14.1, 19.6, 22.9, 25.9, 26.3,27.5, 28.9, 29.0, 29.1, 29.2, 34.0, 36.9, 44.9, 45.7, 51.4, 60.3, 70.8,67.7, 129.9, 131.5, 135.0, 135.2, 174.3

Example 7

Synthesis of methyl(11R,12S,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR34##

To tetrakistriphenylphosphinepalladium prepared in advance in the systemfrom tris(dibenzylideneacetone) dipalladium(0) (92 mg, 0.1 mmol) andtriphenylphosphine (210 mg, 0.8 mmol) were added methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate437 mg, 0.546 mmol) in 1,2-dichloroethane (5 mL) and 2Mtrimethylaluminum in hexane (0.423 mL, 0.846 mmol). This was agitatedfor 3 hours at room temperature. Ether was added to dilute the reactionsolution, then the solution was poured in 1N hydrochloric acid. Thedesired product was extracted with ether from the mixture. The extractwas washed with brine, then was dried over anhydrous sodium sulfate. Thesolution was concentrated under reduced pressure, then was purified bysilica gel column chromotography (2% ethyl acetate/hexane) to obtainmethyl(11R,12S,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(193 mg, 54%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.03, 0.05 (s, 12H), 0.8-0.9 (m, 6H),0.87 (s, 9H), 0.88 (s, 9H), 1.0-1.7 (m, 15H), 1.79 (s, 3H), 2.1-2.7 (m,5H), 3.12 (d, J=7.9 Hz, 1H), 3.66 (s, 3H), 4.0-4.2 (m, 2H), 5.34 (dd,J=8.9 & 15.5 Hz, 1H), 5.52 (dd, J=6.3 & 15.5 Hz, 1H)

Example 8

Synthesis of methyl(11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR35##

To a solution of ice-cooled acetonitrile (2 mL) and pyridine (0.2 mL)was added hydrogen fluoride-pyridine (0.2 mL). To this solution wasaddedmethyl(11R,12S,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dieneacid (196 mg, 0.306 mmol) in pyridine (0.2 mL). The ice bath was removedand the solution was agitated for 15 hours, while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel chromotography (30 to 50% ethyl acetate/hexane) to obtainmethyl(11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(78 mg, 62%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-0.9 (m, 6H), 1.1-1.7 (m, 15H), 1.82(d, J=1.3 Hz, 3H), 2.3-2.8 (m, 4H), 2.31 (t, J=7.4 Hz, 2H), 3.1-3.3 (m,1H), 3.67 (s, 3H), 4.0-4.2 (m, 1H), 4.1-4.3 (m, 1H, 5.50 (dd, J=7.9 &15.2 Hz, 1H), 5.61 (dd, J=6.3 & 15.5 Hz, 1H)

Example 9

Synthesis of(11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid ##STR36##

To methyl(11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(41 mg, 0.099 mmol) in acetone (1 mL) was added pH 8 phosphate buffer(10 mL). To this was further added esterase containing solution (derivedfrom pig's liver, made by Sigma Co., 100 μl). This was agitated at roomtemperature for 15 hours. To the reaction solution was added dilutehydrochloric acid to make the solution pH 4. Further, the solution wasmade saturated by ammonium sulfate, then the desired product wasextracted with ethyl acetate. The extract was washed with brine, thenwas dried over anhydrous sodium sulfate. The solution was concentratedunder reduced pressure, then subjected to thin layer chromotography forseparation (development solution: ethyl acetate) to obtain(11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid (5.4 mg, 14%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H), 1.1-1.7 (m, 15H), 1.82(s, 3H), 2.2-2.8 (m, 4H), 3.1-3.2 (m, 1H), 4.1-4.3 (m, 2H), 5.50 (dd,J=8.3 & 15.5 Hz, 1H), 5.62 (dd, J=6.4 & 15.3 Hz, 1H)

Example 10

Synthesis of methyl(11R,12S,13E,15S,17R)-9-pentyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7thiaprosta-8,13-dienoate##STR37##

1-pentene (110 μl, 1.0 mmol) in tetrahydrofuran (3 mL) was ice-cooled,then 9-borabicyclo[3,3,1]nonane (9-BBN, 0.5M THF solution, 2.0 mL, 1.05mmoL) was added. This was agitated for 6 hours while gradually raisingthe reaction temperature to room temperature. Further, to this wereadded methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid (205 mg, 0.264 mmol), bistriphenylphosphinepalladiumchloride (140mg, 0.2 mmol), and tripotassium phosphate (255 mg, 1.2 mmol) intetrahydrofuran (5 mL) suspension. The reaction mixture was agitated at60° C. for 15 hours. The reaction solution was cooled, then subjected toFlorisil column chromotography to remove the metal complexes. Theresultant solution was concentrated under reduced pressure, then waspurified by silica gel column chromotography (2 to 4% ethylacetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-9-pentyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(71 mg, 38%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.03, 0.05 (s, 12H), 0.8-0.9 (m, 9H),0.87 (s, 9H), 0.88 (s, 9H), 0.9-1.7 (m, 21H), 2.1-2.7 (m, 3H), 3.14 (d,J=8.3 Hz, 1H), 3.66 (s, 3H), 4.0-4.2 (m, 2H), 5.34 (dd, J=8.6 & 15.5 Hz,1H), 5.52 (dd, J=6.3 & 15.2 Hz, 1H)

Example 11

Synthesis of methyl(11R,12S,13E,15S,17R)-9-pentyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR38##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL)was added hydrogen fluoride-pyridine (0.1 mL). To this solution wasadded methyl(11R,12S,13E,15S,17R)-9-pentyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(71 mg, 0.10 mmol) in pyridine (0.1 mL). The ice bath was removed andthe solution was agitated for 15 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromotography (30 to 50% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(24 mg, 50%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 9H), 1.1-1.7 (m, 21H), 2.26(t, J=7.3 Hz, 2H), 2.3-2.8 (m, 4H), 2.31 (t, J=7.3 Hz, 2H), 3.22 (dd,J=3.1 & 7.8 Hz, 1H), 3.67 (s, 3H), 4.0-4.2 (m, 1H), 4.20 (dt, J=8.2 &5.6 Hz, 1H), 5.51 (dd, J=7.8 & 15.3 Hz, 1H), 5.62 (dd, J=6.3 & 15.2 Hz,1H)

¹³ C-NMR (67.5 MHz, δppm, CDCl₃): 14.0, 14.1, 19.5, 22.5, 22.9, 24.5,27.4, 28.0, 29.1, 29.1, 29.5, 29.6, 31.1, 31.6, 33.9, 37.0, 43.1, 44.8,51.5, 60.1, 70.6, 76.4, 127.8, 130.4, 135.6, 144.2, 174.1

Example 12

Synthesis of(11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid ##STR39##

To methyl(11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(20 mg, 0.042 mmol) in acetone (1 mL) was added pH 8 phosphate buffer (5mL). To this was further added esterase containing solution (derivedfrom pig's liver, made by Sigma Co., 50 μl). The solution was agitatedat room temperature for 24 hours. Dilute hydrochloric acid was added tothe reaction solution to make the solution pH 4. Further, the solutionwas made saturated by ammonium sulfate, then the desired product wasextracted with ethyl acetate. The extract was washed with brine, thenwas dried over anhydrous sodium sulfate. The solution was concentratedunder reduced pressure, then subjected to thin layer chromotography forseparation (development solution: ethyl acetate) to obtain(11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid (5.4 mg, 14%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 9H), 1.1-1.7 (m, 21H), 2.26(t, J=7.1 Hz, 2H), 2.3-2.8 (m, 4H), 2.34 (t, J=7.1 Hz, 2H), 3.23 (d,J=5.0 Hz, 1H), 4.1-4.3 (m, 2H), 5.51 (dd, J=7.9 & 15.2 Hz, 1H), 5.62(dd, J=6.4 & 15.3 Hz, 1H)

Example 13

Synthesis of methyl(11R,12S,13E,15S,17R)-9-(3,3-dimethylbutyl)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR40##

3,3-dimethyl-1-butene (129 μl, 1.0 mmol) in tetrahydrofuran (3 mL) wasice-cooled, then 9-BBN (0.5M THF solution, 2.1 mL, 1.05 mmol) was addedand the solution was agitated for 6 hours, while raising the reactiontemperature gradually to room temperature. Further, to this were addedmethyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dieonate(233 mg, 0.3 mmol), bistriphenylphosphinepalladiumchloride (70 mg, 0.1mmol), and tripotassium phosphate (255 mg, 1.2 mmol) in tetrahydrofuran(5 mL) suspension. The reaction mixture was agitated at 60° C. for 15hours. The reaction solution was cooled, then subjected to Florisilcolumn chromotography to remove the metal complexes. The resultantsolution was concentrated under reduced pressure, then was purified bysilica gel column chromotography (2 to 4% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-(3,3-dimethylbutyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(137 mg, 64%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.03 (s), 0.05 (s) . . . 12H, 0.8-0.9(m, 33H), 1.0-1.7 (m, 17H), 2.1-2.7 (m, 8H), 3.13 (d, J=7.6 Hz, 1H),3.66 (s, 3H), 4.0-4.2 (m, 2H), 5.33 (dd, J=8.6 & 15.2 Hz, 1H), 5.52 (dd,J=6.2 & 15.7 Hz, 1H)

Example 14

Synthesis of methyl(11R,12S,13E,15S,17R)-9-(3,3-dimethylbutyl)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR41##

To a solution of ice-cooled acetonitrile (1.5 mL) and pyridine (0.15 mL)was added hydrogen fluoride-pyridine (0.15 mL). To this solution wasadded methyl(11R,12S,13E,15S,17R)-9-(3,3-dimethylbutyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(137 mg, 0.192 mmol) in pyridine (0.15 mL). The ice bath was removed andthe solution was agitated for 15 hours, while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromotography (40 to 50% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-dimethylbutyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(61 mg, 66%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-0.9 (m, 15H), 1.1-1.7 (m, 17H),2.1-2.8 (m, 8H), 3.21 (dd, J=3.3 & 7.9 Hz, 1H), 3.67 (s, 3H), 4.0-4.2(m, 1H), 4.1-4.3 (m, 1H), 5.51 (dd, J=7.9 & 15.5 Hz, 1H), 5.61 (dd,J=6.3 & 15.2 Hz, 1H)

Example 15

Synthesis of methyl(11R,12S,13E,15S,17R)-9-cyano-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR42##

Tetrakis(triphenylphosphine)palladium was prepared in advance in thesystem from tris(dibenzylideneacetone) dipalladium(0) (45.8 mg, 0.05mmol) and triphenylphosphine (105 mg, 0.4 mmol). To this were addedmethyl(11R,12S,13E,15S,17R)-9-trifuloromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(388 mg, 0.5 mmol) and sodium cyanide (36.8 mg, 0.75 mmol) intetrahydrofuran (20 mL) suspension. This was refluxed for 15 hours. Thereaction solution was cooled to room temperature, ether was added todilute it, then the solution was washed with brine. The ether solutionwas dried over anhydrous sodium sulfate, then was concentrated underreduced pressure, then was purified by silica gel column chromatography(5% ethyl acetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-9-cyano-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(170 mg, 52%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.02, 0.05, 0.05 (s, 12H), 0.8-0.9 (m,6H), 0.87 (s, 9H), 0.89 (s, 9H), 1.0-1.7 (m, 15H), 2.32 (t, J=7.4 Hz,2H), 2.49 (dd, J=2.1 & 15.7 Hz, 1H), 2.8-3.2 (m, 3H), 3.24 (dd, J=2.1 &8.4 Hz, 1H), 3.67 (s, 3H), 4.0-4.2 (m, 2H), 5.34 (ddd, J=1.0 & 8.4 &15.3 Hz, 1H), 5.61 (dd, J=5.6 & 15.5 Hz, 1H)

Example 16

Synthesis of methyl(11R,12S,13E,15S,17R)-9-cyano-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dieonate##STR43##

To a solution of ice-cooled acetonitrile (2 mL) and pyridine (0.2 mL)was added hydrogen fluoride-pyridine (0.2 mL). To this solution wasadded methyl(11R,12S,13E,15S,17R)-9-cyano-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(170 mg, 0.261 mmol) in pyridine (0.2 mL). The ice bath was removed andthe solution was agitated for 15 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromatography (40 to 50% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-cyano-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate96 mg, 87%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m,6H), 1.00 (t, J=7.4 Hz, 3H),1.1-1.8 (m, 15H), 2.32 (t, J=7.4 Hz, 2H), 2.56 (ddd, J=1.0 & 4.3 & 15.5Hz, 1H), 2.91 (dd, J=6.3 & 15.5 Hz, 1H), 3.0-3.2 (m, 2H), 3.29 (dd,J=4.0 & 8.6 Hz, 1H), 3.67 (s, 3H), 4.1-4.3 (m, 2H), 5.45 (dd, J=8.6 &15.5 Hz, 1H), 5.65 (dd, J=6.6 & 15.5 Hz, 1H),

¹³ C-NMR (67.5 MHz, δppm, CDCl₃): 14.1, 19.4, 22.9, 24.2, 27.6, 29.0,29.0, 29.2, 30.9, 33.7, 36.8, 42.4, 44.6, 51.6, 61.3, 70.3, 75.9, 101.4,116.7, 126.8, 137.9, 157.5, 174.1

IR (neat) 3775/W3431/S2926/S2858/S2731/W2363/W2208/S1738/S1568/S1456/S1437/S1377/S1261/S1203/S1176/S1049/S970/S862/M729/M

Example 17

Synthesis of methyl(11R,12S,13E,15S,17R)-9-trifluoromethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR44##

Tris(dibenzylideneacetone)dipalladium(0) (11.4 mg, 0.0125 mmol),triphenylphosphine (13.1 mg, 0.05 mmol), zinc (powder) (36.8 mg, 56.3mmol), and methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(218 mg, 0.282 mmol) in tetrahydrofuran (5 mL) were placed in anautoclave reactor, a small sized container of trifluoromethyl iodide wasconnected, and the inside of the reaction vessel was made the samepressure as the inside of the small sized container. The reaction vesselwas made to vibrate in trifluoromethyl iodide atmosphere for 1 hour byan ultrasonic wave washer. Next, the unreacted trifluoromethyl iodide inthe reaction vessel was removed to obtain the reaction solution whichwas passed through Florisil column. The solution thus obtained wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromotography (4to 10% ethyl acetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-9-trifluoromethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(72 mg, 36%).

¹ H-NMR (270 M Hz, δppm, CDCl₃): 0.06 (s, 6H), 0.8-1.0 (m, 6H), 0.88 (s,18H), 1.0-1.7 (m, 15H), 2.31 (t, J=7.1 Hz, 2H), 2.4-2.8 (m, 3H), 2.8-3.0(m, 1H), 3.1-3.3 (m, 1H), 3.67 (s, 3H), 4.0-4.3 (m, 2H), 5.4-5.8 (m,2H),

Example 18

Synthesis of methyl(11R,12S,13E,15S,17R)-9-trifluoromethyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR45##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL)was added hydrogen fluoride-pyridine (0.1 mL). To this solution wasadded methyl(11R,12S,13E,15S,17R)-9-trifluoromethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(36 mg, 0.052 mmol) in pyridine (0.1 mL). The ice bath was removed andthe solution was agitated for 15 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was subjectedto thin layer chromotography (ethyl acetate/hexane=4/1) to obtain methyl(11R,12S,13E,15S,17R)-9-trifluoromethyl-11,12-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(12 mg, 48%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H), 1.1-1.8 (m, 15H), 2.32(t, J=7.3 Hz, 2H), 2.5-2.9 (m, 3H), 3.03 (ddd, J=1.7 & 6.6 & 16.5 Hz,1H), 3.27 (br.d, J=6.3 Hz, 1H), 3.67 (s, 3H), 4.1-4.3 (m, 2H), 5.56 (dd,J=8.3 & 15.5 Hz, 1H), 5.72 (dd, J=5.9 & 15.5 Hz, 1H)

Example 19

Synthesis of methyl(11R,12S,13E,15S,17R)-9-phenethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR46##

Styrene (150 μl, 1.0 mmol) in tetrahydrofuran (3 mL) was ice-cooled,then 9-BBN, (0.5M THF solution, 2.1 mL, 1.05 mmol) was added. This wasagitated for 6 hours while gradually raising the reaction temperature toroom temperature. Further, to this were added methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(233 mg, 0.3 mmol), bistriphenylphosphinepalladiumchloride (70 mg, 0.1mmol), and tripotassium phosphate (255 mg, 1.2 mmol) in tetrahydrofuran(5 mL) suspension. The reaction mixture was agitated at 60° C. for 15hours. The reaction solution was cooled, then subjected to Florisilcolumn chromotography to remove the metal complexes. The obtainedsolution was concentrated under reduced pressure, then was purified bysilica gel column chromotography (2 to 4% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-phenethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(104 mg, 48%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.03 (s), 0.04 (s) . . . 12H, 0.8-1.0(m, 6H), 0.87 (s, 9H), 0.94 (s, 9H), 1.0-1.7 (m, 15H), 2.1-2.7 (m, 10H),3.12 (d, J=7.3 Hz, 1H), 3.66 (s, 3H), 4.0-4.2 (m, 2H), 5.29 (dd, J=8.3 &15.2 Hz, 1H), 5.46 (dd, J=6.3 & 15.2 Hz, 1H), 7.1-7.3 (m, 5H)

Example 20

Synthesis of methyl(11R,12S,13E,15S,17R)-9-phenethyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR47##

To a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 mL)was added hydrogen fluoride-pyridine (0.1 mL). To this solution wasadded methyl(11R,12S,13E,15S,17R)-9-phenethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(52 mg, 0.072 mmol) in pyridine (0.1 mL). The ice bath was removed andthe solution was agitated for 15 hours wile returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution by ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromotography (40 to 50% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-phenethyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(32 mg, 90%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H), 1.1-1.8 (m, 15H),2.2-2.8 (m, 10H), 3.18 (d, J=6.6 Hz, 1H), 3.66 (s, 3H), 4.0-4.1 (m, 1H),4.1-4.3 (m, 1H), 5.44 (dd, J=7.9 & 15.5 Hz, 1H), 5.46 (dd, J=5.9 & 15.5Hz, 1H), 7.1-7.3 (m, 5H)

¹³ C-NMR (67.5 MHz, δppm, CDCl₃): 14.6, 19.9, 23.4, 24.9, 28.5, 29.6,29.6, 30.1, 31.4, 31.5, 34.4, 37.6, 43.8, 45.3, 52.0, 60,5, 71.0, 76.7,126.4, 128.8, 128.9, 129.9, 130.0, 136.1, 141.9, 142.8, 174.6

Example 21

Synthesis of methyl(11R,12S,13E,15S,17R)-9-formyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR48##

Methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(120 mg, 0.154 mmol), palladium acetate (11.2 mg, 0.05 mmol),triphenylphosphine (26 mg, 0.1 mmol), formic acid (12 μl, 0.309 mmol),and triethylamine (65 μl, 063 mmol) in tetrahydrofuran (6 mL) wereplaced in an autoclave into which carbon monoxide gas was pumped underpressure to give the internal pressure of 17 atmospheres. The solutionwas heated and agitated at 80° C. for 15 hours. This was dissolved indimethylformamide (2 ml). Methanol (810 μl, 20 mmol) and triethylamine(139 μl, 1 mmol) were added. This was agitated in carbon monoxideatmosphere (1 atmosphere) at room temperature for further 18 hours. Thereaction vessel was cooled to room temperature, then carbon monoxide inthe reaction vessel was removed, the reaction solution thus obtained waspassed through Florisil column, was concentrated under reduced pressure,and was purified by silica gel column chromotography (2 to 5% ethylacetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-9-formyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoateas a crude (21 mg).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.0-0.2 (m, 12H), 0.8-1.0 (m, 24H),1.1-1.7 (m, 15H), 2.2-2.4 (m, 2H), 2.53 (d, J=17.2 Hz, 1H), 2.6-3.1 (m,3H), 3.49 (d, J=8.3 Hz, 1H), 3.67 (s, 3H), 4.1-4.3 (m, 2H), 5.44 (dd,J=7.9 & 15.7 Hz, 1H), 5.62 (dd, J=5.9 & 15.1 Hz, 1H), 10.04 (s, 1H)

Example 22

Synthesis of methyl(11R,12S,13E,15S,17R)-9-formyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR49##

To a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 mL)was added hydrogen fluoride-pyridine (0.1 mL). To this solution wasadded a mixture of (21 mg) containingmethyl(11R,12S,13E,15S,17R)-9-formyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dieneacid in pyridine (0.1 mL). The ice bath was removed and the solution wasagitated for 15 hours while returning it to room temperature. Thereaction solution was poured into a mixture of ethyl acetate andsaturated aqueous sodium hydrogencarbonate. The desired product wasextracted from this mixed solution with ethyl acetate. The extract waswashed with brine, then dried over anhydrous sodium sulfate. Thesolution was concentrated under reduced pressure, then was subjected tothin layer chromotography (ethyl acetate/hexane=4/1) to obtain methyl(11R,12S,13E,15S,17R)-9-formyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoatein an amount of 3.4 mg (5.2%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 24H) 1.1-1.8 (m, 15H) 2.33(t, J=7.3 Hz, 2H) 2.59 (d, J=16.8 Hz, 1H) 2.6-3.1 (m, 3H) 3.63 (d, J=7.3Hz, 1H) 3.67 (s, 3H) 4.1-4.3 (m, 2H) 5.59 (dd, J=7.6 & 15.5 Hz, 1H) 5.71(dd, J=5.6 & 15.5 Hz, 1H) 10.05 (s, 1H) IR (neat) 3418/S, 2926/S,2858/S, 2723/W, 1738/S, 1651/S, 1556/M, 1437/M, 1379/M, 1257/M, 1203/M,1047/M, 974/M, 862/W, 729/W

EXAMPLE 23

Synthesis of methyl(11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR50##

Methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(388 mg, 0.5 mmol), palladium acetate (11.2 mg, 0.05 mmol), andtriphenylphospine (26.2 g, 0.1 mmol) were dissolved in dimethylformamide(2 mL). To this were added methanol (810 μl, 20 mmol) and triethylamine(139 μl, 1 mmol). This was agitated in carbon monoxide atmosphere (1atmosphere) at room temperature for 18 hours. 10 ml of water was added,the solution separated, and the aqueous phase was extracted with etherand the extract combined with the organic layer. The organic solutionwas washed with brine, then was dried over anhydrous sodium sulfate. Thesolution was concentrated under reduced pressure, then was purified bysilica gel column chromatography (4% ethyl acetate/hexane) to obtainmethyl(11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(134 mg, 38%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.01 (s), 0.03 (s), 0.06 (s), 0.0 7. . .12H0.8-10 (m, 6H) 0.88 (s, 9H) 0.88 (s, 9H) 1.0-1.7 (m, 15H) 2.30 (t,J=7.4 Hz, 2H) 2.54 (d, J=15.5 Hz, 1H) 2.6-2.9 (m, 3H) 3.45 (t, J=6.9 Hz,1H) 3.66 (s, 3H) 3.75 (s, 3H) 4.0-4.2 (m, 1H) 4.07 (d, J=5.3 Hz, 1H)5.48 (dd, J=7.1 & 15.7 Hz, 1H) 5.60 (dd, J=5.8 & 15.7 Hz, 1H)

EXAMPLE 24

Synthesis of methyl(11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR51##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (10 mL) wasadded a hydrogen fluoride-pyridine (0.1 mL). To this solution was addedmethyl(11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(67 mg, 0.097 mmol) in pyridine (0.1 mL). The ice bath was removed andthe solution was agitated for 15 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromatography (40 to 50% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(35 mg, 78%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H) 1.1-1.7 (m, 15H) 2.31(t, J=7.4 Hz, 2H) 2.60 (d, J=16.8 Hz, 1H) 2.7-3.0 (m, 3H) 3.61 (d, J=5.3Hz, 1H) 3.67 (s, 3H) 3.76 (s, 3H) 4.13 (d, J=4.6 Hz, 1H) 4.19 (dt, J=8.6& 4.6 Hz, 1H) 5.5-5.8 (m, 2H)

EXAMPLE 25

Synthesis of methyl(11R,12S,13E,15S,17R)-9-acetyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR52##

Methyl(11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(388 mg, 0.5 mmol), tris(benzylidenacetone)dipalladium (11.4 mg, 0.0125mmol)triphenylphosphine (13.1 mg, 0.05 mmol), lithium chloride (55.3 mg,1.3 mmol), and trimethyltin (69 μl, 0.5 mmol) in tetrahydrofuran (5 mL)were placed in an autoclave reactor. Carbon monoxide gas was pumped intothis to make the internal pressure 5 atmospheres. This was agitated for15 minutes. Next, carbon monoxide in the reactor was removed, then thelid of the autoclave reactor was opened and zinc chloride (68.1 mg, 0.5mmol) was placed in the reaction vessel. Carbon monoxide was againpumped in to 5 atmospheres, then the solution was heated and agitated at75° C. for 15 hours. The reaction vessel was cooled to room temperature,then carbon monoxide in the reaction vessel was removed, the reactionsolution thus obtained was passed through Florisil column, the solutionwas concentrated under reduced pressure, then was purified by silica gelcolumn chromatography (2 to 5% ethyl acetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-9-acetyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoatein an amount of 24 mg (8%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.01 (s), 0.03 (s), 0.07 (s) . . . 12H0.8-1.0 (m, 6H) 0.88 (s, 9H) 0.88 (s, 9H) 1.0-1.7 (m, 15H) 2.26 (s, 3H)2.30 (t, J=7.3 Hz, 2H) 2.56 (d, J=16.2 Hz, 1H) 2.6-3.0 (m, 3H) 3.49 (d,J=6.6 Hz, 1H) 3.66 (s, 3H) 4.0-4.2 (m, 2H) 5.48 (dd, J=6.2 & 15.7 Hz,1H) 5.60 (dd, J=5.6 & 15.5 Hz, 1H)

EXAMPLE 26

Synthesis of methyl(11R,12S,13E,15S,17R)-9-acetyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR53##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL)was added a hydrogen fluoride-pyridine solution (0.1 mL). To thissolution was added methyl(11R,12S,13E,15S,17R)-9-acetyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(12 mg, 0.019 mmol) in pyridine (0.1 mL). The ice bath was removed andthe solution was agitated for 15 hours, while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and a saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution of ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then subjected tothin layer chromatography for separation (ethyl acetate:hexane=3:1) toobtain methyl(11R,12S,13E,15S,17R)-9-acetyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(3.2 mg, 39%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H) 1.1-1.7 (m, 15H) 2.28(s, 3H) 2.31 (t, J=7.3 Hz, 2H) 2.64 (d, J=16.5 Hz, 1H) 2.7-3.0 (m, 2H)3.03 (dd, J=5.1 & 16.3 Hz, 1H) 3.6-3.7 (m, 1H) 3.67 (s, 3H) 4.1-4.3 (m,2H) 5.5-5.8 (m, 2H)

EXAMPLE 27

Synthesis of methyl(11R,12S,13E,15S,17R)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR54##

Methyl(11R,12S,13E,15S,17)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(233 mg, 0.3 mmol), bistriphenylphosphinepalladium(II)acetate (45 mg,0.06 mol), formic acid (22.6 μl, 0.6 mmol), and triethylamine (125 μl,0.9 mmol) in dimethylformamide (1 mL) were agitated at 60° C. for 3hours. The reaction solution was cooled and subjected to Florisil columnchromatography to remove the metal complexes. The solution thus obtainedwas concentrated under reduced pressure, then was purified by silica gelcolumn chromatography (2% ethyl acetate/hexane) to obtain methyl(11R,12S,13E,15S,17R)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(150 mg, 79%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.00 (s), 0.05 (s) . . . 12H 0.8-0.9 (m,6H) 0.87 (s, 9H) 0.89 (s, 9H) 1.1-1.8 (m, 15H) 2.2-2.4 (m, 3H) 2.6-2.8(m, 3H) 3.10 (d, J=6.6 Hz, 1H) 3.66 (s, 3H) 4.1-4.3 (m, 2H) 5.27 (d,J=1.7 Hz, 1H) 5.34 (dd, J=9.4 & 15.3 Hz, 1H) 5.56 (dd, J=6.3 & 15.5 Hz,1H)

EXAMPLE 28

Synthesis of methyl(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate##STR55##

To a solution of ice-cooled acetonitrile (1.5 mL) and pyridine (0.15 mL)was added hydrogen fluoride-pyridine (0.15 mL). To this solution wasadded methyl(11R,12S,13E,15S,17R)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate(150 mg, 0.238 mmol) in pyridine (0.15 mL). The ice bath was removed andthe solution was agitated for 15 hours, while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromatography (40 to 50% ethyl acetate/hexane) toobtain methyl(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(82 mg, 86%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H) 1.1-1.8 (m, 15H) 2.2-2.4(m, 3H) 2.6-2.8 (m, 3H) 3.-3.2 (m, 1H) 3.67 (s, 3H) 4.1-4.3 (m, 2H) 5.27(d, J=2.0 Hz, 1H) 5.46 (dd, J=8.9 & 15.2 Hz, 1H) 5.56 (dd, J=7.3 & 15.2Hz, 1H) ¹³ C-NMR (67.5 MHz, δppm, CDCl₃): 14.1, 19.6, 22.9, 24.4, 28.2,28.4, 29.0, 29.0, 31.1, 33.8, 36.8, 39.9, 44.6, 51.4, 60.0, 70.7, 78.2,118.4, 130.1, 136.7, 138.1, 174.0.

EXAMPLE 29

Synthesis of(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid ##STR56##

To methyl(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate(37.2 mg, 0.093 mmol) in acetone (1 mL) was added pH 8 phosphate buffer(10 mL). To this was further added esterase containing solution (derivedfrom pig's liver, made by Sigma Co., 100 μl). This was agitated at roomtemperature for 15 hours. Dilute hydrochloric acid was added to thereaction solution to make the solution pH 4. Further, The solution wasmade saturated by ammonium sulfate, then the target produce wasextracted with ethyl acetate. The extract was washed with brine, thenwas dried over anhydrous sodium sulfate. The solution was concentratedunder reduced pressure, then subjected to thin layer chromatography forseparation (development solution: ethyl acetate) to obtain(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoicacid (4.6 mg, 12%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 0.8-1.0 (m, 6H) 1.1-1.8 (m, 15H) 2.2-2.4(m, 3H) 2.6-2.8 (m, 3H) 3.1-3.2 (m, 1H) 4.1-4.3 (m, 2H) 5.32 (d, J=1.3Hz, 1H) 5.50 (dd, J=8.4 & 15.3 Hz, 1H) 5.65 (dd, J=6.4 & 15.3 Hz, 1H)

EXAMPLE 30

Synthesis ofmethyl(11R,12S,13E,15S)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR57##

Methyl(11R,12S,13E,15S)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(230 mg, 0.3 mmol), bistriphenylphosphinepalladium(II)acetate (45 mg,0.06 mmol), formic acid (27.6 mg), and triethylamine (91 mg) indimethylformamide (1 mL) were agitated at 60° C. for 3 hours. Thereaction solution was cooled and subjected to Florisil columnchromatography to remove the metal complexes. The obtained solution wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromatography (3.5% ethyl acetate/hexane) to obtain methyl(11R,12S,13E,15S)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(134 mg, 74%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.20 (s, 3H) -0.07 (s, 3H) 0.01 (s, 6H)0.82 (s, 9H) 0.88 (s, 9H) 1.3-1.5 (m, 2H) 1.52-1.75 (m, 4H) 2.2-2.4 (m,3H) 2.55-2.8 (m, 5H) 3.08 (dd, J=1.9 & 8.7 Hz, 1H) 3.66 (s, 3H) 4.1-4.17(m, 1H) 4.22-4.29 (m, 1H) 5.27 (dd, J=1.0 & 1.0 Hz, 1H) 5.39 (ddd, J=1.0& 8.9 & 15.5 Hz, 1H) 5.62 (dd, J=15.5 & 5.4 Hz, 1H) 7.1-7.3 (m, 5H)

EXAMPLE 31

Synthesis of methyl(11R,12S,13E,15S)-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR58##

To a solution of ice-cooled acetonitrile (1.0 mL) and pyridine (0.25 mL)was added hydrogen fluoride-pyridine (0.25 mL). To this solution wasadded methyl(11R,12S,13E,15S)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(120 mg) in pyridine (0.25 mL). The ice bath was removed and thesolution was agitated for 19 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogen carbonate. The desiredproduce was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromatography (55% ethyl acetate/hexane) to obtainmethyl(11R,12S,13E,15S)-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(58 mg, 78%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 1.35-1.5 (m, 2H) 1.6-1.72 (m, 4H) 1.84(br-d, J=5.6 Hz, 1H) 2.32 (t, J=7.3 Hz, 2H) 2.34 (br, 1H) 2.65-2.95 (m,5H) 3.08 (dd, J=3.0 & 7.9 Hz, 1H) 3.67 (s, 3H) 4.1-4.2 (br, 1H) 4.3-4.4(br, 1H) 5.30 (dd, J=2.3 & 4.0 Hz, 1H) 5.49 (ddd, J=2.3 & 8.6 & 15.2 Hz,1H) 5.71 (dd, J=6.3 & 15.2 Hz, 1H) 7.2-7.35 (m, 5H)

EXAMPLE 32

Synthesis of methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR59##

Methyl(11R,12S,13E)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoatesynthesized using the racemate(1E)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butene as thestarting material in accordance with the method of Example 4 was used.To tetrakistriphenylphosphinepalladium prepared in advance in the systemfrom tris(dibenzylideneacetone) dipalladium(0) (132 mg, 0.12 mmol) andtriphenylphosphine (265 mg, 1.0 mmol) were added methyl(11R,12S,13E)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(486 mg, 0.635 mmol) in 1,2-dichloroethane (10 mL) and 1.0M trimethylaluminum in hexane (1.0 mL, 1.0 mmol). This was agitated at 50° C. for 2hours. Ether was added to dilute the reaction solution, then thesolution was poured in 1N hydrochloric acid. The desired product wasextracted with ether from the mixture. The extract was washer withbrine, then was dried over anhydrous sodium sulfate. The solution wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromatography (4% ethyl acetate/hexane) to obtain methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(305 mg, 76%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.25 (s, 3H) -0.10 (s, 3H) 0.04 (s, 6H)0.82 (s, 9H) 0.87 (s, 9H) 1.27-1.68 (m, 6H) 1.79 (s, 3H) 2.15-2.45 (m,2H) 2.29 (t, 2H, J=7.3 Hz) 2.52-2.70 (m, 2H) 2.70-2.81 (m, 2H) 3.11 (d,1H, J=8.3 Hz) 3.66 (s, 3H) 3.97-4.08 (m, 1H) 4.19-4.30 (m, 1H) 5.39 (dd,1H, J=15.3, 8.6 Hz) 5.57 (dd, 1H, J=15.3, 5.6 Hz) 7.10-7.29 (m, 5H)

EXAMPLE 33

Synthesis of methyl(11R,12S,13E)-9-methyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR60##

To a solution of ice-cooled acetonitrile (2 mL) and pyridine (0.5 mL)was added hydrogen fluoride-pyridine (0.5 mL). To this solution wasadded methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(305 mg, 0.48 mmol) in pyridine (0.5 mL). The ice bath was removed andthe solution was agitated for 14 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate. Theextract was washed with brine, then dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, then was purifiedby silica gel column chromatography (ethyl acetate/hexane) to obtain the15-position stereoisomers of methyl(11R,12S,13E)-9-methyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoateseparately (less polar compounds: 75 mg, 39%; more polar compounds: 76mg, 39%). ¹ H-NMR (270 MHz, δppm, CDCl₃): less polar compounds 1.20-1.80(m, 6H) 1.81 (s, 3H) 1.85 (br.s, 1H) 2.19-2.30 (m, 1H) 2.31 (t, 2H,J=7.3 Hz) 2.40-2.53 (m, 1H) 2.55-2.74 (m, 2H) 2.78-2.95 (m, 2H) 3.2 (d,1H, J=8.3 Hz) 3.66 (s, 3H) 3.92-4.03 (m, 1H) 4.30-4.42 (m, 1H) 5.44 (dd,1H, J=15.5, 8,6 Hz) 5.65 (dd, 1H, J=15.5, 6.3 Hz) 7.18-7.36 (m, 5H) morepolar compounds 1.35-1.71 (m, 6H) 1.82 (s, 3H) 2.00 (br.s, 1H) 2.22-2.33(m, 1) 2.31 (t, 2H, J=7.3 Hz) 2.38-2.51 (m, 1H) 2.53-2.75 (m, 2H)2.75-2.94 (m, 2H) 3.21 (d, 1H, J=7.3 Hz) 3.66 (s, 3H) 4.04-4.12 (m, 1H)4.32-4.44 (m, 1H) 5.52 (dd, 1H, J=15.5, 8.3 Hz) 5.67 (dd, 1H, J=15.5,6.3 Hz) 7.19-7.35 (m, 5H)

EXAMPLE 34

Synthesis of(11R,12S,13E)-9-methyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid ##STR61##

Of the two types of isomers of the methyl (11R,12S,13E)-9-methyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoateobtained in Example 33, the more polar compound (30.6 mg, 0.076 mmol)was dissolved in an acetone (1 mL) then pH 8 phosphate buffer (10 mL)was added. To this was further added esterase containing solution(derived from pig's liver, made by Sigma Co., 10 drops). This wasagitated at room temperature for 15 hours. Dilute hydrochloric acid wasadded to the reaction solution to make the solution pH 4. Further, thesolution was made saturated by ammonium sulfate, then the desiredproduct was extracted with ethyl acetate. The extract was washed withbrine, then was dried over anhydrous sodium sulfate. The solution wasconcentrated under reduced pressure, then subjected to HPLC (normalbonded phase column; hexane/ethanol/acetic acid, 80:20:0.1) to obtain(11R,12S,13E)-9-methyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoicacid (15 mg, 51%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 1.30-1.82 (m, 6H) 1.81 (s, 3H) 2.21-2.47(m, 2H) 2.33 (t, 2H, J=7.3 Hz) 2.50-2.83 (m, 2H) 2.85-2.93 (m, 2H)3.15-3.24 (m, 1H) 3.53 (br, 2H) 3.75 (s, 3H) 4.06 (dt, 1H, J=6.9, 3.3Hz) 4.36 (dt, 1H, J=6.6, 6.6 Hz) 5.51 (dd, 1H, J=15.5, 7.9 Hz) 5.65 (dd,1H, J=15.5. 6.6 Hz) 7.16-7.35 (m, 5H)

EXAMPLE 35

Synthesis of methyl(11R,12S,13E)-9-cyclopropyl-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR62##

Cyclopropyl bromide (0.40 mL, 5.0 mmol) was disolved in 25 mL of etherand cooled to -78° C. To this was added 1.50M tert-butyllithium (0.35mL, 5.3 mmol). This was agitated at -78° C. for 3 hours to give acyclopropyllithium solution. This was added to a solution of CuCN (233mg, 2.60 mmol) dissolved in 45 ml of dried ether at -78° C. This wasagitated at -50° C. for 30 minutes, then again cooled to -78° C. Methyl(11R,12S,13E)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate[synthesized using the racemate(1E)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butane as a startingmaterial in accordance with the method of Example 4] in dry ether (2 mL)was added. This was agitated for 15 hours while gradually raising thetemperature to room temperature. The reaction solution was poured into30 ml of a mixture of saturated aqueous ammonium sulfate andconcentrated ammonia water (9:1) to end the reaction. The mixture wasseparated, then the aqueous layer was extracted with ether (30 mL). Theextract was combined with the organic layer and was washed with brine,then dried over anhydrous magnesium sulfate. This was concentrated underreduced pressure, then was purified by silica gel column chromatography(0.5% ethyl acetate/hexane), then was subjected to HPLC (normal bondedphase column; 1.5% ethyl acetate/hexane) to obtain methyl(11R,12S,13E)-9-cyclopropyl-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(15-position stereomixture: 32 mg 10%).

¹ N-NMR (270 MHz, δppm, CDCl₃): -0.23 (s, 3H) -0.10 (s, 3H) 0.02 (s, 6H)0.45-0.60 (m, 2H) 0.64-0.75 (m, 2H) 0.81 (s, 9H) 0.86 (s, 9H) 1.20-1.69(m, 6H) 1.97-2.11 (m, 1H) 2.18-2.80 (m, 6H) 2.30 (t, J=7.3 Hz, 2H)3.09-3.17 (m, 1H) 3.6 (s, 3H) 4.91-4.03 (m, 1H) 4.19-4.30 (m, 1H)5.33-5.45 (m, 1H) 5.58 (dd, J=15.5, 6.3 Hz, 1H) 7.13-7.30 (m, 5H)

EXAMPLE 36

Synthesis of methyl(11R,12S,13E)-9-cyclopropyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR63##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.25 mL)was added hydrogen fluoride-pyridine solution (0.25 mL). To thissolution was added methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-cyclopropyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(32 mg, 0.049 mmol) in pyridine (0.25 mL). The ice bath was removed andthe solution was agitated for 17 hours, while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduce was extracted from this mixed solution with ethyl acetate, waswashed with brine, then was dried over anhydrous sodium sulfate. Thiswas concentrated under reduced pressure, then subjected to HPLC (normalbonded phase column ZORBAX-SIL; 5% ethyl acetate/hexane) to obtain15-position stereoisomers of methyl(11R,12S,13E)-9-cyclopropyl-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoateseparately (less polar compounds: 3 mg, 14%; more polar compounds: 6.9mg, 33%).

¹ H-NMR (270 MHz, δppm, CDCl₃): less polar (HPLC) compounds 0.47-0.65(m, 2H) 0.66-0.78 (m, 2H) 1.23-2.09 (m, 8H) 2.25-2.40 (m, 1H) 2.31 (t,J=7.3 Hz, 2H) 2.41-2.68 (m, 2H) 2.76-2.93 (m, 2H) 3.15-3.26 (m, 1H) 3.66(s, 3H) 3.97-4.06 (m, 1H) 4.31-4.44 (m, 1H) 5.53 (dd, J=15.5, 7.6 Hz,1H) 5.68 (dd, J=15.5, 5.9 Hz, 1H) 7.18-7.36 (m, 5H) more polar (HPLC)compounds 0.46-0.65 (m, 2H) 0.66-0.78 (m, 2H) 1.32-2.08 (m, 8H)2.23-2.38 (m, 1H) 2.31 (t, J=7.6 Hz, 2H) 2.43-2.71 (m, 2H) 2.86-2.95 (m,2H) 3.12-3.24 (m, 1H) 3.66 (s, 3H) 3.83-3.95 (m, 1H) 4.31-4.43 (m, 1H)5.44 (dd, J=15.5, 8.6 Hz, 1H) 5.66 (dd, J=15.5, 6.6 Hz, 1H) 7.15-7.36(m, 5H)

EXAMPLE 37

Synthesis of methyl(13E,15S)-15-(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR64##

(1E,3S)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butene (250 mg)in ether (2.5 mL) was cooled to -78° C., then tert-butyllithium (1.50mol/L, 0.858 mL) was added. This was agitated at -78° C. for 2 hours.Further, to this were added 1-hexynylcopper (I) (93 mg) andhexamethylphosphorus triamide (234 μl) in ether (3.5 mL). This wasfurther agitated at -78° C. for a further 1 hour to give a copperreagent. To the copper reagent thus obtained was added drop-wise2-(5-methoxycarbonylpentylthio)-2-cyclopenten-1-one (159 mg) intetrahydrofuran (5.0 mL). This reaction mixture was agitated at -78° C.for 30 minutes, then the reaction temperature was raised and wasagitated at -50° to -30° C. for 2 hours. To the conjugate adduct thusobtained was added at -50° C. N-phenyltrifluoromethanesulfonimide (620mg) in tetrahydrofuran (6 mL). This was agitated for 1 hour, whilegradually raising the reaction temperature to room temperature. Thereaction solution was poured into saturated aqueous ammonium sulfate(100 m) to end the reaction. The mixture was separated, then the aqueoussolution was extracted with ether. The extract was combined with theorganic layer, then dried over anhydrous magnesium sulfate. This wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromatography (5% ethyl acetate/hexane) to obtain methyl(13E,15S)-15-(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(12-position stereomixture: 239 mg, 59%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.21 (s, 3/2H) -0.20 (s, 3/2H) -0.10(s, 3/2H) -0.08 (s, 3/2H) 0.83 (s, 9H) 1.3-1.8 (m, 8H) 2.31 (t, 2H,J=7.4 Hz) 2.1-2.75 (m, 6H) 3.3 (br, 1H) 3.66 (s, 3H) 4.26 (t-like, 1H,J=6.1 Hz) 5.37-5.65 (m, 2H) 7.1-7.3 (m, 5H)

EXAMPLE 38

Synthesis of methyl(13E,15S)-15-(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR65##

To tetrakistriphenylphosphine palladium prepared in advance in thereaction system from tris(dibenzylidenacetone)(chloroform)dipalladium(0)(65 mg, 0.063 mmol) and triphenylphosphine (131 mg, 0.51 mmol) wereadded methyl(13E,15S)-15-(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(239 mg, 0.38 mmol) in 1,2-dichloroethane (6.0 mL) and 1.02M trimethylaluminum in hexane (0.550 mL, 0.57 mmol). This was agitated at 50° C.for 1 hour. Ether was added to dilute the reaction solution, then thesolution was poured into 0.5N hydrochloric acid. The desired product wasextracted with ether, was washed with brine, then was dried overanhydrous sodium sulfate. The solution was concentrated under reducedpressure, then was purified by silica gel column chromatography (5%ethyl acetate/hexane) to obtain methyl(13E,15S0-15-(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(12-position stereomixture: 144 mg, 76%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.22 (s, 5/4H) -0.20 (s, 7/4H) -0.13(s, 5/4H) -0.19 (s, 7/4H) 0.80 (s, 15/4H) 0.81 (s, 21/4H) 1.2-1.7 (m,8H) 1.78 (s, 3H) 2.30 (t, 2H, J=7.4 Hz) 2.00-2.65 (m, 4H) 2.74 (d-like,2H, J=7.5 Hz) 3.28 (br, 1H) 3.66 (s, 3H) 4.27-4.3 (m, 1H) 5.37-5.53 (m,2H) 7.1-7.35 (m, 5H)

EXAMPLE 39

Synthesis of methyl(13E,15S)-15-hydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate##STR66##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.25 mL)was added hydrogen fluoride-pyridine (0.25 mL). To this solution wasadded methyl(13E,15S)-15-(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(140 mg) in pyridine (0.25 mL). The ice bath was removed and thesolution was agitated for 20 hours while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate, waswashed with brine, then was dried over anhydrous sodium sulfate. Thiswas concentrated under reduced pressure and subjected to HPLC (reversedphase partition column InertsilPREP-ODS; 70% water/acetonitrile) toobtain 12-position stereoisomers of methyl(13E,15S-15-hydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-7thiaprosta-8,13-dienoateseparately (less polar compounds: 36 mg; more polar compounds: 28 mg).

¹ H-NMR (270 MHz, δppm, CDCl₃): less polar (HPLC) compounds 1.35-1.75(m, 8H) 1.80 (s, 3H) 2.0-2.15 (m, 2H) 2.30 (t, 2H, J=7.6 Hz) 2.2-2.65(m, 3H) 2.84 (ddd, 2H, J=6.6 Hz) 3.3 (br, 1H) 3.66 (s, 3H) 4.28-4.38 (m,1H) 5.5-5.65 (m, 2H) 7.18-7.35 (m, 5H) more polar (HPLC) compounds1.3-1.75 (m, 8H) 1.79 (s, 3H) 1.97-2.14 (m, 2H) 2.30 (t, 2H, J=7.5 Hz)2.17-2.65 (m, 3H) 2.83 (d, 2H, J=24 Hz, 13.5 Hz, 6 Hz) 3.3 (br, 1H) 3.66(s, 3H) 4.3-4.4 (m, 1H) 5.5-5.7 (m, 2H) 7.2-7.35 (m, 5H)

EXAMPLE 40

Synthesis of methyl(11R,12S)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate##STR67##

1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-butane (702 mg) in ether(4.0 mL) was cooled to -78° C., then tert-butyllithium (1.50 mol/L, 2.40mL) was added. This was agitated at -78° C. for 1.5 hours. Further, tothis were added 1-hexynylcopper (I) (260 mg) and hexamethylposphorustriamide (654μl) in ether (10 mL). This was agitated at -78° C. for afurther 1 hour to give copper reagent. To the copper reagent thusobtained was drop-wise added(4R)-tert-butyldimethyl-siloxy-2-(5-methoxycarbonylpentylthio)-2-cyclopenten-1-one(559 mg) in tetrahydrofuran (15 mL). This reaction mixture was agitatedat -78° C. for 30 minutes, then the reaction temperature was raised andthe solution was agitated at -50 to -30° C. for 30 minutes. To theobtained conjugate adduct was added at -50° C.N-phenyltrifluoromethanesulfonimide (1.45 g) in tetrahydrofuran (15 ml).The solution was agitated for 1 hour while raising the reactiontemperature to room temperature. The reaction solution was poured intosaturated aqueous ammonium sulfate (100 mL) to end the reaction. Themixture was separated, then the aqueous solution was extracted withether. The extract was combined with the organic layer, then dried overanhydrous magnesium sulfate. This was concentrated under reducedpressure, then was purified by silica gel column chromatography (3%ethyl acetate/hexane) to obtain methyl(11R,12)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate(15-position stereomixture: 888 mg, 77%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.06-0.01 (m, 12H) 0.83 (s, 9H) 0.85(s, 9H) 1.2-1.7 (m, 10H) 2.28 (t, 2H, J=7.6 Hz) 2.35-2.95 (m, 7H) 3.64(s, 3H) 3.8 (m, 1H) 4.02 (br-t, 1H, J=6.3 Hz) 7.1-7.3 (m, 5H)

EXAMPLE 41

Synthesis of methyl(11R,12S)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate##STR68##

To tetrakistriphenylphosphine palladium prepared in advance in thereaction system fromtris(dibenzylideneacetone)(chloroform)dipalladium(0) (95 mg, 0.091 mmol)and triphenylphosphine (191 mg, 0.72 mmol) were added methyl(11R,12S)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate(423 mg, 0.55 mmol) in 1,2-dichloroethane (10 mL) and 1.02Mtrimethylaluminum in hexane (0.830 mL, 0.83 mmol). This was agitated at60° C. for 1 hour. Ether was added to dilute the reaction solution, thenthe solution was poured into 0.5N hydrochloric acid. The desired productwas extracted with ether, was washed with brine, then was dried overanhydrous sodium sulfate. The solution was concentrated under reducedpressure, then was purified by silica gel column chromatography (3%ethyl acetate/hexane) to obtain methyl(11R,12S)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate(15-position stereomixture: 216 mg, 62%).

¹ H NMR (270 MHz, δppm, CDCl₃): -0.08 (s, 3H) -0.57 (s, 3H) -0.01 (s,3H) 0.01 (s, 3H) 0.83 (s, 9H) 0.84 (s, 9H) 1.2-1.7 (m, 10H) 1.76 (s, 3H)2.1-2.75 (m, 7H) 2.28 (t, 2H, J=7.6 Hz) 3.65 (s, 3H) 3.75-3.85 (m, 1H)3.95-4.05 (m, 1H) 7.1-7.3 (m, 5H)

EXAMPLE 42

Synthesis of methyl (11R,12S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate##STR69##

To a solution of ice-cooled acetonitrile (1.5 mL) and pyridine (0.4mL)was added hydrogen fluoride-pyridine (0.4 mL). To this solution wasadded methyl(11R,12S)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate(214 mg) in pyridine (0.4 mL). The ice bath was removed and the solutionwas agitated for 20 hours while returning it to room temperature. Thereaction solution was poured into a mixture of ethyl acetate andsaturated aqueous sodium hydrogencarbonate. The desired product wasextracted from this mixed solution with ethyl acetate, was washed withbrine, then was dried over anhydrous sodium sulfate. This wasconcentrated under reduced pressure , then was purified by silica gelcolumn chromatography (55% ethyl acetate/hexane) to obtain methyl(11R,12S)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8-enoate(15-position stereomixture: 117 mg, 85%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 1.2-2.15 (m, 12H) 2.30 (t, 2H, J=7.3 Hz)2.2-2.9 (m, 7H) 3.65 (s, 1H) 3.75-3.95 (m, 1H) 4.1-4.2 (br, 1H)7.15-7.35 (m, 5H)

EXAMPLE 43

Synthesis of(3S,4R)-4-(tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-cyclopentenyltrifluoromethanesulfonate##STR70##

(1E)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butene (406 mg) inether (3.0 mL) was cooled to -78° C., then tert-butyllithium (1.50mol/L, 1.60 ml) was added. This was agitated at -78° C. for 1 hour.Further, to this were added 1-hexynylcopper (I) (174 mg) andhexamethylphosphorus triamide (436 μl) in ether (10 mL). This wasfurther agitated for 1 hour at -78° C. to give a copper reagent. To thecopper reagent thus obtained was added drop-wise(4R)-tert-butyldimethylsiloxy-2-(5-hexylthio)-2-cyclopenten-1-one (329mg) in tetrahydrofuran (10 mL). This reaction mixture was agitated at-78° C. for 30 minutes, then the reaction temperature was raised and thesolution was agitated at -50 to -30° C. for 2 hours. To the conjugateadduct thus obtained was added at -50° C.N-phenyltrifluoromethanesulfonimide (925 mg) in tetrahydrofuran (10 mL).This was then agitated for 18 hours, while raising the reactiontemperature to room temperature. The reaction solution was poured intosaturated aqueous ammonium sulfate (70 mL) to end the reaction. Themixture was separated, then the aqueous solution was extracted withether. The extract was combined with the organic layer, then dried overanhydrous magnesium sulfate. This was concentrated under reducedpressure, then was purified by silica gel column chromatography (2%ethyl acetate/hexane) to obtain(3S,4R)-4-(tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-cyclopentenyltrifluoromethanesulfonate(476 mg, 66%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.21 (s, 3/2H) -0.20 (s, 3/2H) -0.09(s, 3/2H) -0.8 (s, 3/2H) 0.05 (s, 6H) 0.84 (s, 9/2H) 0.85 (s, 9/2H) 0.88(s, 9H) 0.86 (t, 3H, J=8 Hz) 1.2-1.6 (m, 8H) 2.75 (d, 2H, J=6.6 Hz)2.4-3.0 (m, 4H) 3.16 (d-like, 2H, J=7.9 Hz) 4.0 (br, 1H) 4.25-4.35 (m,1H) 5.35-5.50 (m, 1H) 5.63-5.73 (m, 1H) 7.15-7.35 (m, 5H)

EXAMPLE 44

Synthesis of(3S,4R)-4-(tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-methyl-1-cyclopentene##STR71##

To tetrakistriphenylphosphine palladium prepared in advance in thereaction system fromtris(dibenzylideneacetone)(chloroform)dipalladium(0) (68 mg, 0.065 mmol)and triphenylphosphine (138 mg, 0.52 mmol) were added(3S,4R)-4-(tert-butyldimethylsiloxy-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-cyclopentenyltrifluoromethanesulfonate(470 mg, 0.65 mmol) in 1,2-dichloroethane (6 mL) and 1.02Mtrimethylaluminum in hexane (0.956 mL, 0.98 mmol). This was agitated at50° C. for 1.5 hours. Ether was added to dilute the reaction solution,then the solution was poured into 0.5N hydrochloric acid. The desiredproduct was extracted with ether, was washed with brine, then was driedover anhydrous sodium sulfate. The solution was concentrated underreduced pressure, then was purified by silica gel column chromatography(1% ethyl acetate/hexane) to obtain(3S,4R)-4-tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-methyl-1-cyclopentene(314 mg, 83%).

¹ H -NMR (270 MHz, δppm, CDCl₃): -0.24 (s, 3H) -0.23 (s, 3H) -0.11 (s,3H) -0.10 (s, 3H) 0.81 (s, 9/2H) 0.83 (s, 9/2H) 0.87 (s, 9H) 0.86 (t,3H, J=8 Hz) 1.2-1.7 (m, 8H) 1.79 (s, 3H) 2.20 (d, 1H, J=16.5 Hz)2.32-2.46 (m, 1H) 2.51-2.69 (m, 2H) 2.75 (d, 2H, J=6.6 Hz) 3.13 (d, 1H,J=7.9 Hz) 3.95-4.05 (m, 1H) 4.19-4.29 (m, 1H) 4.34-4.45 (m, 1H) 5.54(dd, 1H, J=15.6 Hz, 6.1 Hz) 7.1-7.3 (m, 5H)

EXAMPLE 45

Synthesis of(3S,4R)-2-hexylthio-4-hydroxy-3-[(1E)-4-phenyl-3-hydroxy-1-butenyl]-1-methyl-1-cyclopentene##STR72##

To a solution of ice-cooled acetonitrile (2 ml) and pyridine (0.5 mL)was added hydrogen fluoride-pyridine (0.5 mL). To this solution wasadded(3S,4R)-4-(tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-methyl-1-cyclopentene(295 mg) in pyridine (1.5 mL). The ice bath was removed and the solutionwas agitated for 20 hours while returning it to room temperature. Thereaction solution was poured into a mixture of ethyl acetate andsaturated aqueous sodium hydrogencarbonate. The desired product wasextracted from this mixed solution with ethyl acetate and was washedwith brine, then was dried over anhydrous sodium sulfate. This wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromatography (30% ethyl acetate/hexane) to obtain stereoisomersof(3S,4R)-2-hexylthio-4-hydroxy-3-[(1E)-4-phenyl-3-hydroxy-1-butenyl]-1-methyl-1-cyclopenteneseparately (less polar compounds: 48.6 mg, 27%; more polar compounds:53.5 mg, 30%).

¹ H-NMR (270 MHz, δppm, CDCl₃): less polar compounds 0.88 (t, 3H, J=6.8Hz) 1.15-1.55 (m, 8H) 1.69 (br, 1H) 1.81 (s, 3H) 2.03 (br, 1H) 2.2-2.90(m, 6H) 3.14-3.24 (m, 1H) 4.06 (br, 1H) 4.34 (q-like, 1H, J=6.4 Hz) 5.53(dd, 1H, J=15.6 Hz, 8.3 Hz) 5.64 (dd, 1H, J=15.6 Hz, 6.3 Hz) 7.15-7.35(m, 5H) more polar compounds 0.88 (t, 3H, J=6.8 Hz) 1.15-1.55 (m, 8H)1.67 (br, 1H) 1.81 (s, 3H) 1.85 (br, 1H) 2.25 (dd, 1H, J=16.8 Hz, 3.0Hz) 2.38-2.52 (m, 1H) 2.53-2.74 (m, 2H) 2.85 (dd-like, 2H, J=6.8 Hz, 3.6Hz) 3.18 (br-d, 1H, J=7.9 Hz) 3.92-4.02 (m, 1H) 4.35 (q-like, 1H, J=6.6Hz) 5.45 (dd, 1H, J=15.5 Hz, 8.6 Hz) 5.65 (dd, 1H, J=15.5 Hz, 6.2 Hz)7.15-7.35 (m, 5H)

EXAMPLE 46

Synthesis of methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-sulfinylprosta-8,13-dienoate##STR73##

To a 30 mL flask was added methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-thiaprosta-8,13-dienoate(101 mg, 0.16 mmol) in dichloromethane (3 mL). This was ice-cooled, thenm-chloroperbenzoic acid (36 mg, 0.21 mmol) was added. This was agitatedfor 5 hours under ice-cooling, then saturated aqueous sodiumhydrogencarbonate (20 mL) was added and the resultant mixture wasextracted with ethyl acetate (30 mL). The extract was dried overanhydrous magnesium sulfate, filtered, concentrated, then was purifiedby silica gel column chromatography (hexane/ethyl acetate 7:3) to obtainmethyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-sulfinylprosta-8,13-dienoate(78 mg, 77%) as a colorless oily substance.

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.25 (s, 3/4H) -0.24 (s, 3/4H) -0.23(s, 3/4H) -0.22 (s, 3/4H) -0.13 (s, 3/4H) -0.10 (s, 3/2H) -0.09 (s,3/4H) 0.04 (s, 3H) 0.05 (s, 3H) 0.82 (s, 9/4H) 0.83 (s, 9/2H) 0.84 (s,9/4H) 0.87 (s, 9/4H) 0.87 (s, 9/2H) 0.88 (s, 9/4H) 1.25-1.85 (m, 6H)2.32 (t, J=7.3 Hz, 2H) 2.33-2.85 (m, 7H) 3.02-3.11 (m, 1/2H) 3.35-3.44(m, 1/2H) 3.65 (s, 3/2H) 3.66 (s, 3/2H) 4.12-4.35 (m, 2H) 5.34-5.52 (m,1H) 5.55-5.73 (m, 1H) 6.38 (br.s, 1H) 7.10-7.30 (m, 5H)

EXAMPLE 47

Synthesis of methyl(11R,12S,13E)-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-sulfinylprosta-8,13-dienoate##STR74##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.25 mL)was added hydrogen fluoride-pyridine (0.25 mL). To this solution wasadded methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-16-phenyl-17,18,19,20-tetranol-7-sulfinylprosta-8,13-dienoate(20.1 mg, 0.033 mmol) in pyridine (0.25 mL). The ice bath was removedand the solution was agitated for 15 hours, while returning it to roomtemperature. The reaction solution was poured into a mixture of ethylacetate and saturated aqueous sodium hydrogencarbonate. The desiredproduct was extracted from this mixed solution with ethyl acetate, waswashed with brine, then was dried over anhydrous sodium sulfate. Thiswas concentrated under reduced pressure and subjected to HPLC (normalbonded phase column ZORBAX-SIL; hexane/ethanol/acetic acid, 80:20:0.1)to obtain methyl(11R,12S,13E)-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranol-7-sulfinylprosta-8,13-dienoate(8.0 mg, 60%).

¹ H-NMR (270 MHz, δppm, CDCl₃): 1.35-1.85 (m, 6H) 2.25-2.85 (m, 8H)3.17-3.25 (s, 1/2H) 3.36-3.50 (s, 1/2H) 3.64 (s, 3/2H) 3.66 (s, 3/2H)4.05-4.40 (m, 2H) 5.38-5.62 (m, 1H) 5.64-5.79 (m, 1H) 6.42 (br.s, 1H)7.15-7.37 (m, 5H)

EXAMPLE 48

Synthesis of methyl(11R,12R,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate##STR75##

(1E)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butene (388 mg) inether (3.0 mL) was cooled to -78° C., then tert-butyllithium (2.1 mol/L,1.2 mL) was added. The solution was agitated at -78° C. for 1.5 hours.Further, to this were added 1-hexynylcopper (I) (144 mg) andhexamethylphosphorus triamide (327 μL) in ether (5.0 mL). The solutionwas agitated at -78° C. for a further 1.5 hours to give copper reagent.To the copper reagent thus obtained was drop-wise added(4R)-tert-butyldimethylsiloxy-2-(5-methoxycarbonylhexyl)-2-cyclopenten-1-one(256 mg) in tetrahydrofuran (5.0 ml). This reaction mixture was agitatedat -78° C. for 1 hour, then the reaction temperature was raised to -40°C. The progress of the reaction was confirmed, then to the conjugateadduct thus obtained was added at -40° C.N-phenyltrifluoromethanesulfonimide in tetrahydrofuran (0.3M, 6.0 mL).This was agitated for 1 hour while gradually raising the reactiontemperature to room temperature. The reaction solution was poured intosaturated aqueous ammonium sulfate (10 mL) to end the reaction. Themixture was separated, then the aqueous solution was extracted withether. The extract was combined with the organic layer, then dried overanhydrous magnesium sulfate. This was concentrated under reducedpressure, then was purified by silica gel column chromatography (1%-5%ethyl acetate/hexane) to obtain methyl(11R,12R,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate(15-position stereomixture: 308 mg, 57%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.24 (s, 3H) -0.12 (s, 3H) 0.04 (d,J=2.0 Hz, 6H) 0.81 (d, J=5.6 Hz, 9H) 0.87 (s, 9H) 1.15-1.41 (m, 8H)1.56-1.66 (m, 1H) 2.32-2.48 (m, 2H) 2.29 (t, J=7.6 Hz, 2H) 2.75-2.92 (m,1H) 2.29 (d, J=6.6 Hz, 2H) 2.94-3.04 (m, 1H) 3.66 (s, 3H) 3.94-4.05 (m,1H) 4.19-4.29 (m, 1H) 5.23-5.35 (m, 1H) 5.44-5.56 (m, 5H) 7.13-7.30 (m,5H)

EXAMPLE 49

Synthesis of methyl(11R,12R,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate##STR76##

To tetrakistriphenylphosphine palladium prepared in advance in thereaction system fromtris(dibenzylideneacetone)(chloroform)dipalladium(0) (85.4 mg, 0.082mmol) and triphenylphosphine (172 mg, 0.65 mmol) were added methyl(11R,12R,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate(308 mg, 0.41 mmol) in 1,2-dichloroethane (8.0 mL) and 1.0Mtrimethylaluminum in hexane (0.7 mL, 0.7 mmol). This was agitated for 5hours at 50° C. and for a further 15 hours at room temperature. Etherwas added to dilute the reaction solution, then the solution was pouredinto 0.5N hydrochloric acid (30 mL). The desired product was extractedwith ether, was washed with brine, then was dried over anhydrous sodiumsulfate. The solution was concentrated under reduced pressure, then waspurified by silica gel column chromatography (5% ethyl acetate/hexane)to obtain methyl(11R,12R,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate(15-position stereomixture: 75 mg, 30%).

¹ H-NMR (270 MHz, δppm, CDCl₃): -0.24 (s, 3H) -0.12 (s, 3H) 0.04 (d,J=2.0 Hz, 6H) 0.81 (d, J=5.6 Hz, 9H) 0.87 (s, 9H) 1.15-1.41 (m, 8H)1.56-1.66 (m, 1H) 1.62 (s, 3H) 2.12-2.24 (m, 1H) 2.29 (t, J=7.6 Hz, 2H)2.42-2.58 (m, 1H) 2.29 (d, J=6.6 Hz, 2H) 2.94-3.04 (m, 1H) 3.66 (s, 3H)3.94-4.05 (m, 1H) 4.19-4.29 (m, 1H) 5.23-5.35 (m, 1H) 5.44-5.56 (m, 1H)7.13-7.30 (m, 5H)

EXAMPLE 50

Synthesis of methyl(11R,12R,13E)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate##STR77##

To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.2 mL)was added hydrogen fluoride-pyridine (0.25 mL). To this solution wasadded methyl(11R,12R,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoate(74 mg) in pyridine (0.2 mL). The ice bath was removed and the solutionwas agitated for 15 hours, while returning it to room temperature. Thereaction solution was poured into a mixture of ethyl acetate andsaturated aqueous sodium hydrogencarbonate. The desired product wasextracted from this mixed solution with ethyl acetate, was washed withbrine, then was dried over anhydrous sodium sulfate. This wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromatography (50% ethyl acetate/hexane) to obtain 15-positionstereoisomers of methyl(11R,12R,13E)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranolprosta-8,13-dienoateseparately (less polar compounds: 15 mg; more polar compounds: 19 mg).Total yield 73%.

¹ H-NMR (270 MHz, δppm, CDCl₃): less polar compounds 1.1-1.4 (m, 8H)1.5-1.8 (m, 2H) 1.61 (s, 3H) 1.55-1.71 (m, 1H) 1.70-1.95, (m, 2H)2.12-2.25 (m, 1H) 2.30 (t, J=7.2 Hz, 2H) 2.50-2.64 (m, 1H) 2.82 (d,J=6.3 Hz, 2H) 2.96-3.07 (m, 1H) 3.65 (s, 3H) 3.85-3.95 (m, 1H) 4.27-4.38(m, 1H) 5.25-5.40 (m, 1H) 5.50-5.65 (m, 1H) 7.15-7.33 (m, 5H) more polarcompounds 1.1-1.4 (m, 8H) 1.5-1.8 (m, 2H) 1.61 (s, 3H) 1.9-2.1 (m, 3H)2.12-2.25 (m, 1H) 2.30 (t, J=7.2 Hz, 2H) 2.50-2.64 (m, 1H) 2.82 (d,J=6.3 Hz, 2H) 2.96-3.07 (m, 1H) 3.65 (s, 3H) 3.95-4.07 (m, 1H) 4.27-4.38(m, 1H) 5.30-5.45 (m, 1H) 5.50-5.63 (m, 1H) 7.15-7.33 (m, 5H)

EXAMPLE 51

Synthesis of methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoate##STR78##

(1E)-1-iodo-3-(tert-butyldimethylsiloxy)-4-phenyl-1-butene (470 mg) inether (3.0 mL) solution was cooled to -78° C., then tert-butyllithium(2.1 mol/L, 1.2 mL) was added. The solution was agitated at -78° C. for1.5 hours. Further, to this were added 1-hexynylcopper (I) (175 mg) andhexamethylphosphorus triamide (390 μL) in an ether (6.0 mL). theresultant mixture was agitated at -78° C. for a further 1.5 hours togive a copper reagent. To the copper reagent thus obtained was addeddrop-wise (4R)-tert-butyldimethylsiloxy)-2-(3-(methoxycarbonylmethyloxy)propylthio)-2-cyclopenten-1-one (350 mg) in tetrahydrofuran (18 mL).This reaction mixture was agitated at -78° C. for 1 hour, then thereaction temperature was raised to -40° C. The progress of the reactionwas confirmed, then to the resultant conjugate adduct was added at 40°C. N-phenyltrifluoromethane-sulfonimide in tetrahydrofuran (0.3M, 6.5mL). This was agitated for 1 hour, while raising the reactiontemperature to room temperature. The reaction solution was poured intosaturated aqueous ammonium sulfate (10 mL) to end the reaction. Themixture was separated, then the aqueous layer was extracted with ether.The extract and the organic layer were combined and dried over anhydrousmagnesium sulfate. This was concentrated under reduced pressure, thenwas purified by silica gel column chromatography (1%-5% ethylacetate/hexane) to obtain methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoate(15-position stereomixture: 268 mg, 37%).

¹ H-NMR (270 MHz, δppm, CDCl₃):

-0.22 (s, 3H)

-0.09 (s, 3H)

0.05 (d, J=3.0 Hz, 6H)

0.79 (d, J=3.0 Hz, 9H)

0.82 (s, 9H)

1.7-1.9 (m, 1H)

2.38-2.45 (m, 1H)

2.55-2.92 (m, 2H)

2.70 (d, J=8.6 Hz, 2H)

3.09-3.16 (m, 1H)

3.52-3.60 (m, 2H)

3.70 (s, 3H)

3.93-3.98 (m, 1H)

4.02 (s, 2H)

4.22-4.30 (m, 1H)

5.38-5.44 (m, 1H)

5.57-5.68 (m, 1H)

7.08-7.22 (m, 5H)

EXAMPLE 52

Synthesis of methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoate##STR79##

To tetrakistriphenylphosphine palladium prepared in advance in thereaction system from tris(dibenzylideneacetone) (chloroform)dipalladium(0) (108 mg, 0.104 mmol) and triphenrylphosphine (218 mg,0.83 mmol) were added methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsoloxy)-9-trifluoromethanesulfonyloxy-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dieneoate(400 mg, 0.52 mmol) in 1,2-dichloroethane (8.0 mL) and 1.0Mtrimethylaluminum in hexane (0.85 mL, 0.7 mmol). This was agitated at50° C. for 5 hours then at room temperature for 15 hours. Ether wasadded to dilute the reaction solution, then the solution was poured into0.5N hydrochloric acid (30 mL). The desired product was extracted withether, was washed with brine, then was dried over anhydrous sodiumsulfate. The solution was concentrated under reduced pressure, then waspurified by silica gel column chromatography (5% ethyl acetate/hexane)to obtain methyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoate(15-position stereomixture: 120 mg, 36%).

¹ H-NMR (270 MHz, δppm, CDCl₃):

-0.23 (s, 3H)

-0.10 (s, 3H)

0.03 (d, J=2.6 Hz, 6H)

0.78 (d, J=2.6 Hz, 9H)

0.82 (s, 9H)

1.65-1.86 (m, 1H)

1.76 (s, 3H)

2.13-2.32 (m, 1H)

2.42-2.68 (m, 2H)

2.71 (d, J=6.6 Hz, 2H)

3.07-3.12 (m, 1H)

3.47-3.60 (m, 2H)

3.71 (s, 3H)

3.92-4.01 (m, 1H)

4.03 (s, 2H)

4.13-4.22 (m, 1H)

5.25-5.48 (m, 1H)

5.53-5.48 (dd, J=15.5 Hz, 6.3 Hz, 1H)

7.05-7.22 (m, 5H)

EXAMPLE 53

Synthesis of methyl(11R,12S,13E)-11,15-dihyroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoate##STR80##

To a mixture of ice-cooled acetonitrile (1 mL) and pyridine (0.3 mL) wasadded hydrogen fluoride-pyridine (0.3 mL). to This solution was addedmethyl(11R,12S,13E)-11,15-bis(tert-butyldimethylsiloxy)-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dienoate(120 mg) in pyridine (0.3 mL). The ice bath was removed and the solutionwas agitated for 15 hours, while returning it to room temperature. Thereaction solution was poured into a mixture of ethyl acetate andsaturated aqueous sodium hydrogencarbonate. The desired product wasextracted from this mixed solution with ethyl acetate, was washed withbrine, then was dried over anhydrous sodium sulfate. This wasconcentrated under reduced pressure, then was purified by silica gelcolumn chromatography (50% ethyl acetate/hexane) to obtain 15-positionstereoisomers of methyl(11R,12S,13E)-11,15-dihydroxy-9-methyl-16-phenyl-17,18,19,20-tetranol-3-oxa-7-thiaprosta-8,13-dieneacid separately (less polar compounds: 42 mg; more polar compounds: 28mg). Total yield 89%.

¹ H-NMR (270 MHz, δppm, CDCl₃):

less polar compounds

1.7-1.9 (s, 3H)

1.82 (s, 3H)

2.15-2.35 (m, 3H)

2.50-2.95 (m, 4H)

3.17-3.28 (m, 1H)

3.59 (t, J=6.9 Hz, 2H)

3.74 (s, 3H)

3.91-4.02 (m, 1H)

4.07 (s, 2H)

4.29-4.39 (m, 1H)

5.35-5.48 (m, 1H)

5.60-5.71 (m, 1H)

7.15-7.33 (m, 5H)

more polar compounds

1.7-1.9 (s, 2H)

1.82 (s, 3H)

2.15-2.35 (m, 3H)

2.50-2.95 (m, 4H)

3.17-3.28 (m, 1H)

3.59 (t, J=6.9 Hz, 2H)

3.74 (s, 3H)

4.0-4.1 (m, 1H)

4.07 (s, 2H)

4.29-4.39 (m, 1H)

5.30-5.45 (m, 1H)

5.60-5.71 (m, 1H)

7.15-7.33 (m, 5H)

EXAMPLE 54

Measurement of Inhibitory Activity of Cell Migration Caused by MCP-1

To evaluate the activity of the test compounds listed in the followingtable in inhibiting cell migration, the cell migration caused by themonocyte chemotactic protein MCP-1/MCAF was measured using humanpremonocyte-derived leukemia cells THP-1 (ATCCTIB203) as migrating cellsand the method of FALK et al. (J. Immunol. Methods, vol. 33, pp. 239 to247 (1980)) as follows. That is, to the upper chamber (200 μl) of a96-well microchemotaxis chamber (made by Neuroprobe Co.) was added 2×10⁶/ml THP-1 cells (10% fetal calf serum (FCS) containing RPMI-1640 medium(made by Flow Laboratories Co.), while to the lower chamber (35 μl) wasplaced recombinant human MCP-1 (made by Peprotech Co.) diluted by thesame solution to give a final concentration of 20 ng/ml. Between the twochambers, a polycarbonate filter (pore size 5 μm, PVP-free, made byNeuroprobe Co.) was affixed. Incubation was performed at 37° C. in thepresence of 5% CO₂ for 2 hours. The filter was taken out and the cellsmigrating to the lower surface of the filter were immobilized andstained by a DiffQuick solution (made by Kokusai Shiyaku Co.) Next, aBreedmeter (made by Molecular Device Co.) was used for measurement at ameasurement wavelength of 550 nm and the mean value of three wells wasfound and used as an indicator of the number of migrating cells. At thistime, the test compound was added to the upper chamber together withTHP-1 cells in various concentrations to find the cell migrationinhibitory activity. The cell migration inhibition % was found bydividing the (number of migrating cells caused by MCP-1 added to thelower chamber in the case of addition of the test compound to the upperchamber)-(number of migrating cells in the case of no test compoundadded to the upper chamber and no MCP-1 added to the lower chamber) by(number of migrating cells caused by MCP-1 added to the lower chamber inthe case of no test compound added to the upper chamber)-(number ofmigrating cells in the case of no test compound added to the upperchamber and no MCP-1 added to the lower chamber). The concentration ofthe compound exhibiting 50% inhibition was made the inhibition rateIC₅₀. The results are shown in the following tables.

                                      TABLE 1                                     __________________________________________________________________________    Cell Migration Inhibitory Activity                                            Test compound                  IC.sub.50 (M)                                  __________________________________________________________________________    1 #STR81##                     7.2 × 10.sup.-8                          2 #STR82##                     2.6 × 10.sup.-8                          3 #STR83##                     4.5 × 10.sup.-7                          4 #STR84##                     6.0 × 10.sup.-7                          5 #STR85##                     2.5 × 10.sup.-6                          6 #STR86##                     1.9 × 10.sup.-7                          __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Cell Migration Inhibitory Activity                                            Test compound               IC.sub.50 (M)                                     ______________________________________                                        7 #STR87##                  4.7 × 10.sup.-7                             8 #STR88##                  2.1 × 10.sup.-7                             9 #STR89##                  1.3 × 10.sup.-8                             0 #STR90##                  1.5 × 10.sup.-7                             1 #STR91##                  3.8 × 10.sup.-7                             ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________    Cell Migration Inhibitory Activity                                            Test compound                      IC.sub.50 (M)                              __________________________________________________________________________    2 #STR92##               Less polar isomer                                                                       2.1 × 10.sup.-7                      3 #STR93##               More polar isomer                                                                       1.0 × 10.sup.-8                      4 #STR94##               Compound of Ex. 34                                                                      1.6 × 10.sup.-8                      5 #STR95##               Less polar isomer                                                                       2.0 × 10.sup.-7                      6 #STR96##               More polar isomer                                                                       1.5 × 10.sup.-8                      7 #STR97##                         1.2 × 10.sup.-7                      __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Cell Migration lnhibitory Activity                                            Test compound                     IC.sub.50 (M)                               __________________________________________________________________________    8 #STR98##               More polar isomer                                                                      6.5 × 10.sup.-8                       9 #STR99##               More polar isomer                                                                      3.6 × 10.sup.-7                       __________________________________________________________________________

EXAMPLE 55

Measurement of Inhibitory Activity of Cell Migration Caused by PDGF

To evaluate the activity of the test compounds listed in the followingtable to inhibit cell migration caused by PDGF, the migrating cellscaused by human platelet derived growth factor (PDGF) were measured inthe following way using the vascular smooth muscle cells derived fromnormal human arteries (made by Kurabo) and according to the method ofMaCarthy et al. (J. Cell. Biol. 97, 772-777 (1983)). That is, aTranswell Chamber (Costar Co., registered trademark) was used to measurethe inhibitory action. The chamber was divided into two layers, upperand lower, by a 8 μm pore size membrane filter (PVP-free polycarbonatefilter, Nucleopore Co., registered trademark). The filter was precoatedon its lower surface with 5 μg of rat tail collagen type 1 (BectonDickinson Co.) To the upper chamber (100 μl) was added a 1.5×10⁶ /mlsuspension of cells (DMEM (made by Flow Laboratories Co.) containing0.1% BSA (made by Nakalai Tesque Co.) In the lower chamber (600 μl) wasplaced the same solution diluted by human PDGF (made by BectonDickinson) to give a final concentration of 10 ng/ml. At this time, thetest compound was added in different concentrations to both the upperand lower chambers. The chambers were incubated at 37° C. under 5% CO₂for 6 hours, then the filter was removed, fixed in 99.7% methanol, thenstained with hematoxylin and eosin. The cells on the upper surface ofthe filter were removed by wiping with a cotton swab and the cells thathad migrated to the lower surface of the filter were counted under ahigh output microscope (×200). Usually, five fields were counted perfilter. The migrated cells were shown by the average cell count of fivefields. The inhibition rate (%) was shown by the ratio of the count ofthe migrating cells in the case of treatment by the test compound to thecount of migrating cells in the case of no treatment. The inhibitionrate (%) of the test compounds at a concentration of 10-8M are shown inTable 5.

                                      TABLE 5                                     __________________________________________________________________________    Inhibitory Activity of Cell Migration Caused by PDGF                          Test compound                      IC.sub.50 (M)                              __________________________________________________________________________    0 #STR100##              More polar isomer                                                                       8.1 × 10.sup.-8                      1 #STR101##              Compound of Ex. 34                                                                      7.3 × 10.sup.-8                      __________________________________________________________________________

EXAMPLE 56

Thickening of Intima of Carotid Artery of Rat Due to Balloon Catheter

Test compound: Methyl(11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoato##STR102##

The test was performed in the following manner in accordance with themethod of Crose et al. (Lab. Invest., vol. 49, p. 206, 1983). MaleWistar rats having a body weight of 300 to 350 g were used. The neck ofeach rat was opened under anesthesia by sodium pentobarbitol, then aballoon catheter (Fogarty, 2F) was inserted from the right externalcarotid artery, until the starting portion of the common carotid artery.The balloon was expanded by physiological saline to such an extentcausing a light resistance, then the catheter was pulled out in thatstate up to the carotid artery to give trauma to the intima. Thisprocedure was repeated three times, then the catheter was withdrawn andthe external carotid artery was sewn up. After 14 days, the chest wasopened under anesthesia by diethyl ether, refluxing was performed fromthe aorta by a Carnoa solution (methanol:chloroform:acetic acid=6:3:1),then the right common carotid artery was excised and immobilized byneutral formalin solution. The immobilized carotid artery was dyed byElasticavan Gieson dye, then the areas of the Media and thickenedportion of the Intima were measured by an image resolution device(LUZEX2D).

The test compound began to be administered subcutaneously at a rate of3.2 μg/rat/hr using a miniosmotic pump buried in the back of the ratfrom 3 days before the surgery and was continued until 11 days after thesurgery. The activity of the test compound in suppressing intimathickening was found from the following formula.

Intima thickening suppression rate (%)=(1-T/C)×100

wherein, T shows the ratio between the area of the thickened portion ofthe intima and the area of the media portion of the rats of the groupadministered the test compound, while C shows that of the control group(group administered solvent) [Intima/Media].

The test results are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                        Activity Suppressing Thickening                                               of Intima in Rats                                                                                  Intima/media                                                                             Suppression                                            No. of      (Average ±                                                                            Rate                                          Drug     examples    standard error)                                                                          (%)                                           ______________________________________                                        Control  12          0.935 ± 0.377                                         Test     10          0.702 ± 0.241                                                                         25                                            compound                                                                      ______________________________________                                    

As is clear from the test results, the test compounds suppressed thethickening of the intima of the veins.

EXAMPLE 57

Measurement of Inhibitory Activity of Platelet Aggregation in Rats

Wistar rats (male, approximately 400 g) were made to fast for 1 day,then the entire blood was taken from the abdominal artery underanesthesia by ether. To this was added a 3.8% aqueous solution of sodiumcitrate in a 1/10 amount followed by immediate mixture. This wascentrifuged at 1000 rpm for 10 minutes. The top layer was used as theplatelet rich plasma. The bottom layer was centrifuged at 3000 rpm for10 minutes and the top layer was used as the platelet poor plasma. Theplatelet rich plasma was diluted by the platelet poor plasma to give aplatelet count of 3.5×10⁸ /mm³. This was used for the measurement. Notethat the platelets were measured using an automatic blood cell counterMEK-4500 (Nihon Koden). The platelet aggregation was measured bymeasuring the turbidity using an NBS HEMATRACER 801 (M. C. Medical). 90μl of the platelets were placed in cuvettes, then 5 μl of the differenttest compounds were added to give the target final concentration, thenthese were heated for 1 minute at 37° C., then 5 μl of an aqueoussolution of 100 μM adenosine 2-phosphoric acid (M. C. Medical) was addedto cause platelet aggregation. The activity inhibiting aggregation wasfound from the following formula:

Aggregation inhibiting rate (%)

={1-(maximum change in turbidity at time of addition of test compound)

÷(maximum change in turbidity at time of no addition of test compound)}

×100

The concentration of the compound exhibiting 50% inhibition was made theIC₅₀. The results are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                        Activity Suppressing Platelet Aggregation                                     (Rats)                                                                        Test compound               IC.sub.50 (M)                                     ______________________________________                                        2 #STR103##                 4.5 × 10.sup.-6                             3 #STR104##                 7.6 × 10.sup.-7                             4 #STR105##                 2.2 × 10.sup.-6                             ______________________________________                                    

INDUSTRIAL APPLICABILITY

Drugs containing as their active ingredients the prostaglandins of thepresent invention and their enantiomers or mixtures of any ratio of theenantiomers or their pharmacologically allowable salts have aninhibitory activity on cell migration caused by chemokines, for example,MCP-1/MCAF and are useful as drugs for the prevention and treatment ofdiseases such as restenosis or reocclusion occurring after trauma to theintima of arteries in agioplasty etc., stenosis or occlusion causedprimarily by formation of atherosclerosis at the coronary artery orcarotid artery etc., and other diseases having as one of theircharacteristics the aggregation of monocytes in the blood at theleasion.

Further, the prostaglandins of the present invention have thecharacteristic biological action of prostaglandin derivatives ofactivity inhibiting platelet aggregation and are useful also as drugsfor the prevention and treatment of diseases for which prostaglandinderivatives were conventionally considered useful such as thrombosis,cardiac infarction, and angina.

We claim:
 1. A prostaglandin having the formula (I): ##STR106## whereinR¹ indicates a C₁ to C₁₀ straight chain or branched alkyl group, a C₃ toC₈ cycloalkyl group, a cyano group, a formyl group, a carboxyl group, aC₁ to C₅ alkyloxycarbonyl group, a C₂ to C₇ alkanoyl group, or a C₁ toC₅ alkyl group substituted with one or more halogen atoms or one or moresubstituted or unsubstituted phenyl groups,Z indicates a hydrogen atomor OR², R² and R³ are the same or different and indicate a hydrogenatom, a tri C₁ to C₇ hydrocarbon silyl group, or a group forming anacetal bond with the oxygen atom of a hydroxy group, R⁴ indicates a C₁to C₈ straight chain or branched alkyl group, a C₂ to C₈ straight chainor branched alkenyl group, a C₂ to C₈ straight chain or branched alkynylgroup, a substituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a straight chain or branched(C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynylgroup) each substituted with a C₁ to C₅ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, or asubstituted or unsubstituted heterocyclic group, Y indicates a C₁ to C₅straight chain or branched alkyl group or CO₂ R⁵, R⁵ indicates ahydrogen atom, a C₁ to C₁₀ straight chain or branched alkyl group, or aC₂ to C₁₀ straight chain or branched alkenyl group, or one equivalentcation, X indicates a methylene group or an oxygen atom, W indicates asulfur atom, a sulfynyl group or a methylene group, and the bondrepresented by a solid line together with a broken line indicates adouble bond or single bond, or an enantiomer thereof or any mixture ofenantiomers at any ratio.
 2. A prostaglandin as claimed in claim 1,wherein, in formula (I), ##STR107## R¹ indicates a C₁ to C₅ straightchain or branched alkyl group, a cyclopropyl group, a cyano group, aformyl group, a methoxycarboxyl group, an acetyl group, atrifluoromethyl group or a phenethyl group,Z indicates a hydrogen atomor OR², R² and R³ may be the same or different and indicate a hydrogenatom or a tert-butyldimethylsilyl group, R⁴ indicates a C₁ to C₈straight chain or branched alkyl group or a benzyl group, Y indicates amethyl group or CO₂ R⁵, R⁵ indicates a hydrogen atom or a methyl group,X indicates a methylene group or an oxygen atom, W indicates a sulfuratom, a sulfinyl group or a methylene group, and the bond represented bya solid line together with a broken line indicates a double bond orsingle bond.
 3. A prostaglandin having the formula (II): ##STR108##wherein V indicates a sulfur atom or a sulfinyl group,Z indicates ahydrogen atom or OR², R² and R³ are the same or different and indicate ahydrogen atom, a tri C₁ to C₇ hydrocarbon silyl group, or a groupforming an acetal bond with the oxygen atom of a hydroxy group, R⁴indicates a C₁ to C₈ straight chain or branched alkyl group, a C₂ to C₈straight chain or branched alkenyl group, a C₂ to C₈ straight chain orbranched alkynyl group, a substituted or unsubstituted phenyl group, asubstituted or unsubstituted C₃ to C₈ cycloalkyl group, or a straightchain or branched (C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂to C₅ alkynyl group) each substituted with a C₁ to C₅ alkoxy group, asubstituted or unsubstituted phenyl group, a substituted orunsubstituted phenoxy group, a substituted or unsubstituted C₃ to C₈cycloalkyl group, or a substituted or unsubstituted heterocyclic group,Y indicates a C₁ to C₅ straight chain or branched alkyl group or CO₂ R⁵,R⁵ indicates a hydrogen atom, a C₁ to C₁₀ straight chain or branchedalkyl group, or a C₂ to C₁₀ straight chain or branched alkenyl group, orone equivalent cation, X indicates a methylene group or an oxygen atom,and the bond represented by a solid line together with a broken lineindicates a double bond or single bond, or an enantiomer thereof or anymixture of enantiomers at any ratio.
 4. A prostaglandin as claimed inclaim 3, wherein, in formula (II), ##STR109## wherein V indicates asulfur atom or a sulfinyl group,Z indicates a hydrogen atom or OR², R²and R³ may be the same or different and indicate a hydrogen atom or atert-butyldimethylsilyl group, R⁴ indicates a C₁ to C₈ straight chain orbranched alkyl group or a benzyl group, Y indicates a methyl group orCO₂ R⁵, R⁵ indicates a hydrogen atom or a methyl group, X indicates amethylene group or an oxygen atom, and the bond represented by a solidline together with a broken line indicates a double bond or single bond.5. A prostaglandin having the formula (III):wherein ##STR110## W¹indicates a sulfur atom or a methylene group, Z indicates a hydrogenatom or OR², R² and R³ are the same or different and indicate a hydrogenatom, a tri C₁ to C₇ hydrocarbon silyl group, or a group forming anacetal bond with the oxygen atom of a hydroxy group, R⁴ indicates a C₁to C₈ straight chain or branched alkyl group, a C₂ to C₈ straight chainor branched alkenyl group, a C₂ to C₈ straight chain or branched alkynylgroup, a substituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a straight chain or branched(C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynylgroup) each substituted with a C₁ to C₅ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, or asubstituted or unsubstituted heterocyclic group, Y indicates a C₁ to C₅straight chain or branched alkyl group or CO₂ R⁵, R⁵ indicates ahydrogen atom, a C₁ to C₁₀ straight chain or branched alkyl group, or aC₂ to C₁₀ straight chain or branched alkenyl group, or one equivalentcation, X indicates a methylene group or an oxygen atom, and the bondrepresented by a solid line together with a broken line indicates adouble bond or single bond, or an enantiomer thereof or any mixtures ofenantiomers at any ratio.
 6. A process for producing a prostaglandinaccording to claim 5, comprising the steps of:(i) reacting(a) anorganocopper compound prepared from an organolithium compound having theformula (IV): ##STR111## wherein R⁴ indicates a C₁ to C₈ straight chainor branched alkyl group, a C₂ to C₈ straight chain or branched alkenylgroup, a C₂ to C₈ straight chain or branched alkynyl group, asubstituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a straight chain or branched(C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynylgroup) each substituted with a C₁ to C₅ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, or asubstituted or unsubstituted heterocyclic group, R³¹ indicates a tri C₁to C₇ hydrocarbon silyl group or a group forming an acetal bond with theoxygen atom of a hydroxy group, and the bond represented by a solid linetogether with a broken line indicates a double or a single bond and acopper reagent of the formula CuQ wherein Q indicates a 1-hexynyl group,a 1-pentynyl group, or a cyano group, with (b) a 2-cyclopentenone havingthe formula (V): ##STR112## wherein Z¹ indicates a hydrogen atom orOR²¹, R²¹ indicates a tri C₁ to C₇ hydrocarbon silyl group or a groupforming an acetal bond with the oxygen atom of a hydroxy group, Y¹indicates a C₁ to C₅ straight chain or branched alkyl group or CO₂R⁵¹,R⁵¹ indicates a C₁ to C₁₀ straight chain or branched alkyl group ora C₂ to C₁₀ straight chain or branched alkenyl group, W¹ indicates asulfur atom, a sulfynyl group or a methylene group, and X indicates amethylene group or an oxygen atom, or an enantiomer thereof or anymixture thereof at any ratio to obtain a reaction product; then(ii)reacting the reaction product of (i) with an sulfonimide having theformula (VI): ##STR113## wherein A indicates a hydrogen atom or achlorine atom and D indicates a nitrogen atom or a methine group, toproduce a compound having the formula (VII): ##STR114## wherein R³¹, R⁴,W¹, X, Y¹, Z¹ and the bond represented by a solid line together with abroken line have the same definitions set forth above, or an enantiomerthereof or any mixture of the enantiomers at any ratio and,(iii)further, optionally, removing the protective group and/or performing ahydrolysis reaction.
 7. A process for producing a prostaglandinaccording to claim 1 or 2, comprising coupling a compound having theformula (VII) ##STR115## wherein R⁴ indicates a C₁ to C₈ straight chainor branched alkyl group, a C₂ to C₈ straight chain or branched alkenylgroup, a C₂ to C₈ straight chain or branched alkynyl group, asubstituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a straight chain or branched(C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynylgroup) each substituted with a C₁ to C₅ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, or asubstituted or unsubstituted heterocyclic group,R³¹ indicates a tri C₁to C₇ hydrocarbon silyl group or a group forming an acetal bond with theoxygen atom of a hydroxy group, Z¹ indicates a hydrogen atom or OR²¹,R²¹indicates a tri C₁ to C₇ hydrocarbon silyl group or a group forming anacetal bond with the oxygen atom of a hydroxy group, Y¹ indicates a C₁to C₅ straight chain or branched alkyl group or CO₂ R⁵¹,R⁵¹ indicates aC₁ to C₁₀ straight chain or branched alkyl group or a C₂ to C₁₀ straightchain or branched alkenyl group, and W¹ indicates a sulfur atom, asulfynyl group or a methylene group, and X indicates a methylene groupor an oxygen atom, and the bond represented by a solid line togetherwith a broken line indicates a double or a single bond, or an enantiomeror any mixture of enantiomers at any ratio and an organoboron compoundhaving the formula (VIII): ##STR116## wherein R¹¹ indicates a C₁ to C₁₀straight chain or branched alkyl group, or a C₁ to C₅ alkyl groupsubstituted with one or more halogen atoms or one or more substituted orunsubstituted phenyl groups, an organolithium compound having theformula:

    (R.sup.12).sub.3 Al

wherein R¹² indicates a C₁ to C₁₀ straight chain or branched alkyl groupor a C₁ to C₅ alkyl group substituted with a substituted orunsubstituted phenyl group an organozinc compound having the formula:

    R.sup.13 ZnI

wherein R¹³ indicates a C₁ to C₁₀ straight chain or branched alkyl groupor a fluorine atom-substituted C₁ to C₅ alkyl group, an organotincompound having the formula:

    R.sup.14 SnBu.sub.3

wherein R¹⁴ indicates a C₁ to C₁₀ straight chain or branched alkyl groupor a C₁ to C₅ alkyl group substituted with a substituted orunsubstituted phenyl group and Bu represents a butyl group or a cyanidehaving the formula:

    LCN

wherein L indicates a sodium atom or a potassium atom in an inert gasatmosphere in the presence of a palladium catalyst to obtain a compoundhaving the formula (I-1): ##STR117## wherein R¹⁵ indicates a C₁ to C₁₀straight chain or branched alkyl group, a cyano group, or a C₁ to C₅alkyl group substituted with one or more halogen atoms or substituted orunsubstituted phenyl groups, and R³¹, R⁴, W¹, X, Y¹, Z¹ and the bondrepresented by a solid line together with a broken line have the samedefinitions set forth above, or an enantiomer thereof or any mixturethereof at any ratio and, optionally, removing the protective groupand/or performing a hydrolysis reaction.
 8. A process for producing aprostaglandin according to claim 1 or 2 comprising:carbonylating acompound having the formula (VII) ##STR118## wherein R⁴ indicates a C₁to C₈ straight chain or branched alkyl group, a C₂ to C₈ straight chainor branched alkenyl group, a C₂ to C₈ straight chain or branched alkynylgroup, a substituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a straight chain or branched(C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynylgroup) each substituted with a C₁ to C₅ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, or asubstituted or unsubstituted heterocyclic group, R³¹ indicates a tri C₁to C₇ hydrocarbon silyl group or a group forming an acetal bond with theoxygen atom of a hydroxy group, Z¹ indicates a hydrogen atom or OR²¹,R²¹indicates a tri C₁ to C₇ hydrocarbon silyl group or a group forming anacetal bond with the oxygen atom of a hydroxy group, Y¹ indicates a C₁to C₅ straight chain or branched alkyl group or CO₂ R⁵¹,R⁵¹ indicates aC₁ to C₁₀ straight chain or branched alkyl group or a C₂ to C₁₀ straightchain or branched alkenyl group, and W¹ indicates a sulfur atom, asulfynyl group or a methylene group, and X indicates a methylene groupor an oxygen atom, and the bond represented by a solid line togetherwith a broken line indicates a double or a single bond, or an enantiomeror any mixture of enantiomers at any ratio in a carbon monoxideatmosphere in the presence of a palladium catalyst to obtain anintermediate, reacting the obtained intermediate with hydrogen gas,ammonium formate or formic acid and a tertiary amine salt to obtain acompound having the formula (I-2): ##STR119## wherein R¹⁶ is a formylgroup and R³¹, R⁴, W¹, X, Y¹, Z¹ and the bond represented by a solidline together with a broken line have the same definitions set forthabove, or an enantiomer thereof or any mixture of enantiomers at anyratio and, optionally, removing the protective group and/or applying ahydrolysis reaction.
 9. A process for producing prostaglandin accordingto claim 1, comprising carbonylating a compound having the formula (VII)##STR120## wherein R⁴ indicates a C₁ to C₈ straight chain or branchedalkyl group, a C₂ to C₈ straight chain or branched alkenyl group, a C₂to C₈ straight chain or branched alkynyl group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted C₃ to C₈cycloalkyl group, or a straight chain or branched (C₁ to C₅ alkyl group,C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynyl group) each substitutedwith a C₁ to C₅ alkoxy group, a substituted or unsubstituted phenylgroup, a substituted or unsubstituted phenoxy group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a substituted orunsubstituted heterocyclic group,R³¹ indicates a tri C₁ to C₇hydrocarbon silyl group or a group forming an acetal bond with theoxygen atom of a hydroxy group, Z¹ indicates a hydrogen atom or OR²¹,R²¹indicates a tri C₁ to C₇ hydrocarbon silyl group or a group forming anacetal bond with the oxygen atom of a hydroxy group, Y¹ indicates a C₁to C₅ straight chain or branched alkyl group or CO₂ R⁵¹,R⁵¹ indicates aC₁ to C₁₀ straight chain or branched alkyl group or a C₂ to C₁₀ straightchain or branched alkenyl group, and W¹ indicates a sulfur atom, asulfynyl group or a methylene group, and X indicates a methylene groupor an oxygen atom, and the bond represented by a solid line togetherwith a broken line indicates a double or a single bond, or an enantiomerthereof or any mixture of enantiomers at any ratio in the presence of aC₁ to C₅ alcohol or water in a carbon monoxide atmosphere and in thepresence of a palladium catalyst to obtain a compound having the formula(I-3): ##STR121## wherein R¹⁷ indicates a carboxyl group or a C₁ to C₅alkoxycarbonyl group and R³¹, R⁴, W¹, X, Y¹, Z¹ and the bond representedby a solid line together with a broken line have the same definitionsset forth above, or an enantiomer thereof or any mixture of enantiomersat any ratio and, optionally, removing the protective group and/orapplying a hydrolysis reaction.
 10. A process for producingprostaglandin according to claim 1 or 2 comprising:reacting a compoundhaving the formula (VII) ##STR122## R⁴ indicates a C₁ to C₈ straightchain or branched alkyl group, a C₂ to C₈ straight chain or branchedalkenyl group, a C₂ to C₈ straight chain or branched alkynyl group, asubstituted or unsubstituted phenyl group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a straight chain or branched(C₁ to C₅ alkyl group, C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynylgroup) each substituted with a C₁ to C₅ alkoxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, or asubstituted or unsubstituted heterocyclic group, R³¹ indicates a tri C₁to C₇ hydrocarbon silyl group or a group forming an acetal bond with theoxygen atom of a hydroxy group, Z¹ indicates a hydrogen atom or OR²¹,R²¹indicates a tri C₁ to C₇ hydrocarbon silyl group or a group forming anacetal bond with the oxygen atom of a hydroxy group, Y¹ indicates a C₁to C₅ straight chain or branched alkyl group or CO₂ R⁵¹,R⁵¹ indicates aC₁ to C₁₀ straight chain or branched alkyl group or a C₂ to C₁₀ straightchain or branched alkenyl group, and W¹ indicates a sulfur atom, asulfynyl group or a methylene group, and X indicates a methylene groupor an oxygen atom, and the bond represented by a solid line togetherwith a broken line indicates a double or a single bond, or an enantiomerthereof or any mixture of enantiomers at any ratio in a carbon monoxideatmosphere with an organoboron compound having the formula (VIII')##STR123## wherein R¹¹¹ indicates a C₁ to C₆ straight chain or branchedalkyl group, an organolithium compound of

    (R.sup.121).sub.3 Al

wherein R¹²¹ indicates a C₁ to C₆ straight chain or branched alkylgroup, or an organozine compound having the formula:

    R.sup.131 ZnI

wherein R¹³¹ indicates a C₁ to C₆ straight chain or branched alkylgroup, or an organotin compound having the formula:

    R.sup.141 SnBu.sub.3

wherein R¹⁴¹ indicates a C₁ to C₆ straight chain or branched alkyl groupand Bu represents a butyl group in the presence of a palladium catalystto obtain an alkanoylated compound having the formula (I-4): ##STR124##wherein R¹⁸ indicates a carboxyl group or a C₂ to C₇ alkanoyl group, andR³¹, R⁴, W¹, X, Y¹, Z¹ and the bond represented by a solid line togetherwith a broken line have the same definitions set forth above, or anenantiomer thereof or any mixture of enantiomers at any ratio and,optionally, removing the protective group and/or applying a hydrolysisreaction.
 11. A process for producing a prostaglandin according to claim3 or 4 comprising:reducing a compound having the formula (VII'):##STR125## R⁴ indicates a C₁ to C₈ straight chain or branched alkylgroup, a C₂ to C₈ straight chain or branched alkenyl group, a C₂ to C₈straight chain or branched alkynyl group, a substituted or unsubstitutedphenyl group, a substituted or unsubstituted C₃ to C₈ cycloalkyl group,or a straight chain or branched (C₁ to C₅ alkyl group, C₂ to C₅ alkenylgroup, or a C₂ to C₅ alkynyl group) each substituted with a C₁ to C₅alkoxy group, a substituted or unsubstituted phenyl group, a substitutedor unsubstituted phenoxy group, a substituted or unsubstituted C₃ to C₈cycloalkyl group, or a substituted or unsubstituted heterocyclic group,R³¹ indicates a tri C₁ to C₇ hydrocarbon silyl group or a group formingan acetal bond with the oxygen atom of a hydroxy group, Z¹ indicates ahydrogen atom or OR²¹,R²¹ indicates a tri C₁ to C₇ hydrocarbon silylgroup or a group forming an acetal bond with the oxygen atom of ahydroxy group, Y¹ indicates a C₁ to C₅ straight chain or branched alkylgroup or CO₂ R⁵¹,R⁵¹ indicates a C₁ to C₁₀ straight chain or branchedalkyl group or a C₂ to C₁₀ straight chain or branched alkenyl group, andX indicates a methylene group or an oxygen atom, and the bondrepresented by a solid line together with a broken line indicates adouble or a single bond, or an enantiomer thereof or any mixture ofenantiomers at any ratio in the presence of a palladium catalyst usingformic acid and further, optionally, removing the protective groupand/or applying a hydrolysis reaction.
 12. A process for producing aprostaglandin according to claim 1, wherein R¹ is a C₃ to C₈ cycloalkylgroup or C₁ to C₁₀ straight chain or branched alkyl group, comprisingthe steps of:(i) reacting (a) a compound having the formula (VII)##STR126## wherein R⁴ indicates a C₁ to C₈ straight chain or branchedalkyl group, a C₂ to C₈ straight chain or branched alkenyl group, a C₂to C₈ straight chain or branched alkynyl group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted C₃ to C₈cycloalkyl group, or a straight chain or branched (C₁ to C₅ alkyl group,C₂ to C₅ alkenyl group, or a C₂ to C₅ alkynyl group) each substitutedwith a C₁ to C₅ alkoxy group, a substituted or unsubstituted phenylgroup, a substituted or unsubstituted phenoxy group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a substituted orunsubstituted heterocyclic group, R³¹ indicates a tri C₁ to C₇hydrocarbon silyl group or a group forming an acetal bond with theoxygen atom of a hydroxy group, Z¹ indicates a hydrogen atom or OR²¹,R²¹indicates a tri C₁ to C₇ hydrocarbon silyl group or a group forming anacetal bond with the oxygen atom of a hydroxy group, Y¹ indicates a C₁to C₅ straight chain or branched alkyl group or CO₂ R⁵¹,R⁵¹ indicates aC₁ to C₁₀ straight chain or branched alkyl group or a C₂ to C₁₀ straightchain or branched alkenyl group, and W¹ indicates a sulfur atom, asulfynyl group or a methylene group, and X indicates a methylene groupor an oxygen atom, and the bond represented by a solid line togetherwith a broken line indicates a double or a single bond, or an enantiomerthereof or any mixture of enantiomers at any ratio with (b) anorganocopper compound having the formula:

    (R.sup.19).sub.2 CuLi or (R.sup.19).sub.2 Cu(CN)Li.sub.2

wherein R¹⁹ indicates a C₃ to C₈ cycloalkyl group or C₁ to C₁₀ straightchain or branched alkyl group to obtain a compound having the formula(I-5): ##STR127## wherein R¹⁹ indicates a C₃ to C₈ cycloalkyl group orC₁ to C₁₀ straight chain or branched alkyl group and R³¹, R⁴, W¹, X, Y¹,Z¹ and the bond represented by a solid line together with a broken linehave the same definitions as set forth above, or an enantiomer thereofor any mixture of enantiomers at any ratio and, optionally,(ii) removingthe protective group and/or applying a hydrolysis reaction.
 13. Apharmaceutical composition for inhibiting cell migration caused by achemokine comprising, as its active ingredient, an effective amount toinhibit cell migration of a prostaglandin having the formula (IX):##STR128## wherein R¹¹¹ indicates a hydrogen atom, a C₁ to C₁₀ straightchain or branched alkyl group, a C₃ to C₈ cycloalkyl group, a cyanogroup, a formyl group, a carboxyl group, a C₁ to C₅ alkyl oxycarbonylgroup, a C₂ to C₇ alkanoyl group, or a C₁ to C₅ alkyl group substitutedwith one or more halogen atoms or substituted or unsubstituted phenylgroups,Z indicates a hydrogen atom or OR², R² and R³ are the same ordifferent and indicate a hydrogen atom, a tri C₁ to C₇ hydrocarbon silylgroup, or a group forming an acetal bond with the oxygen atom of ahydroxy group, R⁴ is a C₁ to C₈ straight chain or branched alkyl group,a C₂ to C₈ straight chain or branched alkenyl group, a C₂ to C₈ straightchain or branched alkynyl group, a substituted or unsubstituted phenylgroup, a substituted or unsubstituted C₃ to C₈ cycloalkyl group, andfurther a straight chain or branched (C₁ to C₅ alkyl group, C₂ to C₅alkenyl group, or a C₂ to C₅ alkynyl group) each substituted with a C₁to C₅ alkoxy group, a substituted or unsubstituted phenyl group, asubstituted or unsubstituted phenoxy group, a substituted orunsubstituted C₃ to C₈ cycloalkyl group, or a substituted orunsubstituted heterocyclic group, Y indicates a C₁ to C₅ straight chainor branched alkyl group or CO₂ R⁵,R⁵ indicates a hydrogen atom, a C₁ toC₁₀ straight chain or branched alkyl group, a C₂ to C₁₀ straight chainor branched alkenyl group, or one equivalent cation, X indicates amethylene group or an oxygen atom, W indicates a sulfur atom, a sulfynylgroup or a methylene group, and the bond represented by a solid linetogether with a broken line indicates a double bond or single bond, oran enantiomer thereof or any mixture of enantiomers at any ratio.